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Cell_Biology_Alberts. Each B cell clone makes Ig molecules with a unique antigen‑binding site. Initially, the Ig molecules are inserted into the plasma membrane and serve as B cell receptors (BCRs) for antigen. Antigen binding to the BCRs, together with co‑stimulatory signals from helper T cells, activates the B cells to proliferate and differentiate into either memory cells or antibody‑secreting effector cells. The effector cells secrete large amounts of antibodies with the same antigen‑binding site as the BCRs. A typical Ig molecule is composed of four polypeptide chains—two identical heavy chains and two identical light chains. Parts of both the heavy and light chains form the two identical antigen‑binding sites. There are multiple classes of Ig (IgA, IgD, IgE, IgG, and IgM), each with a distinctive heavy chain, which determines the


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Cell_Biology_Alberts. Figure 24–30 An example of the DNA rearrangement that occurs in class switch recombination. A B cell making IgM molecules with a V region encoded by a particular assembled VDJ DNA sequence is stimulated to switch to making IgA molecules with the same V region. In the process, it deletes the DNA between the VDJ sequence and the cα-coding sequence. Specific DNA sequences (switch sequences) located upstream of each ch-coding sequence (except cδ, as B cells don't switch from cμ to cδ) can recombine with one another, with the deletion of the intervening DNA, as shown here. As discussed in the text, the recombination process depends on AID, the same enzyme that is involved in somatic hypermutation. When switching from IgM to IgG or Ige, the c-region coding sequences downstream of cγ or cδ, which remain after the DNA deletion, are removed during rNA splicing. combinatorial joining of gene segments combinatorial joining of L and H chains


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Cell_Biology_Alberts. combinatorial joining of gene segments combinatorial joining of L and H chains Figure 24–31 The main mechanisms of Ig diversification in mice and humans. Those shaded in green occur during B cell development in the bone marrow, whereas the two mechanisms shaded in red occur when B cells are stimulated by foreign antigen and helper T cells in germinal centers in peripheral lymphoid organs, either late in a primary response or in a secondary response. biological properties of the Ig class. Each light and heavy chain is composed of a number of Ig domains. The amino acid sequence variation in the variable domains of both light and heavy chains is concentrated in several small hypervariable regions, which form loops at one end of these domains to produce the antigen‑binding site.


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Cell_Biology_Alberts. Igs are encoded by loci on three different chromosomes, each of which is responsible for producing a different polypeptide chain—a κ light chain, a λ light chain, or a heavy chain. Each locus contains separate gene segments that encode different parts of the variable region of the particular Ig chain. Each light‑chain locus contains one or more constant‑ (C‑) region coding sequences and sets of variable (V) and joining (J) gene segments. The heavy‑chain locus contains sets of C‑region coding sequences and sets of V, diversity (D), and J gene segments.


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Cell_Biology_Alberts. During B cell development in the bone marrow, before antigen stimulation, separate gene segments are brought together by site‑specific recombination that depends on a V(D)J recombinase. A VL gene segment recombines with a JL gene segment to produce a DNA sequence coding for the V region of a light chain, and a VH gene segment recombines with a D and a JH gene segment to produce a DNA sequence coding for the V region of a heavy chain. Each of the newly assembled V‑region coding sequences is then co‑transcribed with the appropriate C‑region sequence to produce an RNA molecule that codes for the complete Ig polypeptide chain.


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Cell_Biology_Alberts. By randomly combining inherited gene segments that code for the variable regions during B cell development, humans can make hundreds of different light chains and thousands of different heavy chains. Because the antigen‑binding site is formed where the hypervariable loops of the VL and VH domains come together in the final Ig molecule, the heavy and light chains can potentially pair to form Igs with millions of different antigen‑binding sites. A loss or gain of nucleotides at the site of gene‑segment joining increases this number enormously. The Igs made by such V(D)J recombination before antigen stimulation are IgMs and IgDs with low affinity for binding antigen, and they constitute the primary Ig repertoire.


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Cell_Biology_Alberts. Igs are further diversified following antigen stimulation in peripheral lymphoid organs by the AID‑ and helper‑T‑cell‑dependent processes of somatic hypermutation and class switch recombination, which together produce the high‑affinity IgG, IgE, and IgA Igs that constitute the secondary Ig repertoire. The process of class switching allows the same antigen‑binding site to be incorporated into antibodies that have different tails and therefore different biological properties.


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Cell_Biology_Alberts. Like antibody responses, T-cell-mediated immune responses are exquisitely antigen-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including most antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that have entered the interior of host cells, where they are invisible to B cells and antibodies. Much of the rest of this chapter is concerned with how T cells accomplish this feat.


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Cell_Biology_Alberts. T cell responses differ from B cell responses in at least two crucial ways. First, a T cell is activated by foreign antigen to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of an antigen‑presenting cell (APC), usually a dendritic cell in a peripheral lymphoid organ. One reason T cells require APCs for activation is that the form of antigen they recognize is different from that recognized by the Igs produced by B cells. Whereas Igs can recognize antigenic determinants on the surface of pathogens and soluble folded proteins, for example, T cells can only recognize fragments of protein antigens that have been produced by partial proteolysis inside a host cell. As mentioned earlier, newly formed MHC proteins capture these peptide fragments and carry them to the surface of the host cell, where T cells can recognize them.


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Cell_Biology_Alberts. The second difference is that, once activated, effector T cells act mainly at short range, either within a secondary lymphoid organ or after they have migrated to a site of infection. Effector B cells, by contrast, secrete antibodies that can act far away. Effector T cells interact directly with another host cell in the body, which they either kill (if it is an infected host cell, for example) or signal in some way (if it is a B cell or macrophage, for example). We will refer to such host cells as target cells. As is the case with APCs, target cells must display an antigen bound to an MHC protein on their surface for a T cell to recognize them.


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Cell_Biology_Alberts. There are three main classes of T cells—cytotoxic T cells, helper T cells, and regulatory T cells. When activated, they function as effector cells (see Figure 24–17), each with their own distinct activities. Effector cytotoxic T cells directly kill cells that are infected with a virus or some other intracellular pathogen. Effector helper T cells help stimulate the responses of other immune cells—mainly macrophages, dendritic cells, B cells, and cytotoxic T cells; as we will see, there are a variety of functionally distinct subtypes of helper T cells. Effector regulatory T cells suppress the activity of other immune cells. In this section, we describe these classes and subclasses of T cells and their respective functions. We discuss how they recognize foreign antigens on the surface of APCs or target cells and the crucial part played by MHC proteins in the recognition process. We begin by considering the cell-surface receptors that T cells use to recognize antigen.


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Cell_Biology_Alberts. T cell receptors (TCRs), unlike Igs made by B cells, exist only in membrane-bound form. They are composed of two transmembrane, disulfide-linked polypeptide chains, each of which contains two Ig-like domains—one variable and one constant. On most T cells, the TCRs have one α chain and one β chain (Figure 24–32).


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Cell_Biology_Alberts. The genetic loci that encode the αand β chains are located on different chromosomes. Like an Ig heavy-chain locus (see Figure 24–29), the TCR loci contain separate V, D, and J gene segments (or just V and J gene segments in the case of the α-chain locus), which are brought together by site-specific recombination during T cell development in the thymus. With one exception, T cells use the same mechanisms to generate antigen-binding site diversity of their TCRs as B cells use to generate antigen-binding site diversity of their Igs, and they use the same V(D)J recombinase; thus, humans or mice deficient in this recombinase cannot make functional B or T cells. The mechanism that does not operate in TCR diversification is antigen-driven somatic hypermutation. Thus, the affinities of TCRs tend to be low (Ka ≈ 105–107 liters/mole). Various co-receptors and cell–cell adhesion proteins, however, greatly strengthen the binding of a T cell to an APC or target cell.


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Cell_Biology_Alberts. Figure 24–32 A T cell receptor (TCR) heterodimer. (A) Schematic drawing showing that the receptor is composed of an α and a β polypeptide chain. each chain has a large extracellular part that is folded into two Ig-like domains—one variable (V) and one constant (c). A Vα and a Vβ domain (shaded in blue) form the antigen-binding site. Unlike Igs, which have two binding sites for antigen, Tcrs have only one. The αβ-heterodimer is noncovalently associated with a large set of invariant membrane-bound proteins (not shown), which help activate the T cell when the Tcrs bind their specific antigen (see Figure 24–45B). A typical T cell has about 30,000 Tcrs on its surface. (B) The three-dimensional structure of the extracellular part of a Tcr. The antigen-binding site is formed by the hypervariable loops of both the Vα and Vβ domains (black), and it is similar in its overall dimensions and geometry to the antigen-binding site of an Ig molecule. (B, based on K.c. Garcia et al., Science


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Cell_Biology_Alberts. loops of both the Vα and Vβ domains (black), and it is similar in its overall dimensions and geometry to the antigen-binding site of an Ig molecule. (B, based on K.c. Garcia et al., Science 274:209–219, 1996.)


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Cell_Biology_Alberts. Instead of making α and β chains, a minority of T cells makes a different but related type of TCR heterodimer, composed of γ chains and δ chains. Although these γ/δ T cells normally make up only 5–10% of the T cells in human blood, they can be the dominant T cell population in epithelia (in the skin and gut, for example). They have some properties in common with natural killer (NK) cells and with an enlarging category of T-like cells that have features of both innate and adaptive immune cells, which are sometimes collectively referred to as innate lymphoid cells. The cells in all these categories tend to be enriched in mucosal tissues, respond early to infection, display little immunological memory, and, compared with B and T cells, have surface receptors of restricted diversity. We will not discuss them further.


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Cell_Biology_Alberts. As with BCRs, TCRs are tightly associated in the plasma membrane with a number of invariant membrane-bound proteins that are involved in passing the signal from an antigen-activated receptor to the cell interior. We will discuss these proteins in more detail later, when we consider some of the molecular events involved in T and B cell activation. First, we consider the special ways in which T cells recognize foreign antigen on the surface of an APC or target cell.


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Cell_Biology_Alberts. Generally, naïve T cells, including naïve helper and cytotoxic T cells, proliferate and differentiate into effector cells and memory cells only when they see their specific antigen on the surface of an activated dendritic cell in a peripheral lymphoid organ (Figure 24–33). The activated dendritic cell displays the antigen in a complex with MHC proteins on its surface, along with co-stimulatory proteins (see Figure 24–11). The memory T cells that develop, however, can be activated by the same antigen–MHC complex on the surface of other types of APCs (target cells), including macrophages and B cells—as well as by dendritic cells.


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Cell_Biology_Alberts. Immature dendritic cells are located in most tissues—underlying epithelial layers of the skin and gut, for example—where they are constantly sampling and processing proteins in their environment. They become activated to mature when their pattern recognition receptors (PRRs) encounter pathogen associated molecular patterns (PAMPs) on an invading pathogen or its products. The pathogen or products are ingested, and the microbial proteins are cleaved into peptide fragments, which are loaded onto MHC proteins, as we discuss later. The activated dendritic cells then migrate via the lymph from the site of infection to local lymph nodes or gut-associated lymphoid organs, where they present the foreign antigens, displayed as peptide–MHC complexes on the dendritic cell surface, for recognition by the relevant T cells (see Figure 24–11).


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Cell_Biology_Alberts. Activated dendritic cells display three types of protein molecules on their surface that have a role in activating a T cell to become an effector cell or memory cell (Figure 24–34): (1) MHC proteins, which present foreign peptides to the TCRs; (2) co‑stimulatory proteins, which bind to complementary receptors on the T cell surface; and (3) cell–cell adhesion molecules, which enable a T cell to bind to the dendritic cell for long enough to become activated, typically several hours. In addition, activated dendritic cells secrete a variety of cytokines that influence the type of effector helper T cell that develops, and different types of dendritic cells promote different outcomes (discussed later). T cells recognize Foreign peptides Bound to Mhc proteins


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Cell_Biology_Alberts. T cells recognize Foreign peptides Bound to Mhc proteins MHC proteins capture and display peptide fragments of foreign proteins for presentation to T cells. There are two main classes of MHC proteins, which are structurally and functionally distinct. Class I MHC proteins mainly present foreign peptides to cytotoxic T cells, whereas class II MHC proteins mainly present foreign peptides to helper and regulatory T cells (Figure 24–35). Some class-I-like MHC proteins present microbial lipid and glycolipid antigens to T cells, but they are not encoded within the MHC region of the genome, and we will not consider them further. Figure 24–33 Immunofluorescence micrograph of a dendritic cell in culture. These Apcs derive their name from their long processes, or “dendrites.” The cell has been labeled with a monoclonal antibody that recognizes a surface antigen on these cells. (courtesy of David Katz.)


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Cell_Biology_Alberts. Both class I and class II MHC proteins are heterodimers, in which two extracellular domains form a peptide‑binding groove, which always has a variable small peptide bound in it. In class I MHC proteins, the two domains that form the pep-tide-binding groove are provided by the transmembrane αchain, which is noncovalently associated with a small subunit called β2-microglobulin; in class II MHC proteins, a different α chain and a large noncovalently associated β chain each contribute an extracellular domain to form the peptide-binding groove (Figure 24–36). A TCR binds to both the peptide and the ridges of the binding groove. Humans have three major class I proteins, called HLA‑A, HLA‑B, and HLA‑C, and three class II proteins, called HLA‑DR, HLA‑DP, and HLA‑DQ (HLA stands for human-leukocyte-associated, as these proteins were first demonstrated on human leukocytes). Figure 24–37 shows how the genes that encode these proteins are arranged on human chromosome 6.


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Cell_Biology_Alberts. There are important differences between the class I and class II MHC proteins with regard to the cell types that express them and the origin of the peptides in their peptide-binding grooves. Almost all of our nucleated cells express class I proteins. Their peptide-binding groove displays one of a diverse collection of peptides (typically 8–10 amino acids in length). In a healthy cell, the peptides originate from the cell’s own cytosolic and nuclear proteins that have undergone partial degradation in proteasomes in the processes of normal protein turnover and quality control mechanisms. Some of the peptide fragments produced in this way are actively transported into the lumen of the endoplasmic reticulum (ER), through a specialized transporter in the ER membrane, where they are loaded onto newly synthesized class I MHC α chains; once a peptide binds, the α chain can assemble with its partner chain. The resulting self-peptide–MHC complex is then transported through the Golgi apparatus


Cell_Biology_Alberts

Cell_Biology_Alberts. newly synthesized class I MHC α chains; once a peptide binds, the α chain can assemble with its partner chain. The resulting self-peptide–MHC complex is then transported through the Golgi apparatus to the cell surface. Such complexes are not dangerous, however, because the cytotoxic T cells that could recognize fragment MHC of foreign MHC of foreign protein


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Cell_Biology_Alberts. Figure 24–34 The three general types of proteins on the surface of an activated dendritic cell involved in activating a T cell. Although only membrane-bound co-stimulatory molecules are shown, activated dendritic cells also secrete soluble co-stimulatory molecules. The invariant polypeptide chains that are always stably associated with the Tcr are not shown; they are illustrated in Figure 24–45B and Movie 24.7. Figure 24–35 Recognition by T cells of foreign peptides bound to MHC proteins. cytotoxic T cells recognize foreign peptides in association with class I Mhc proteins, whereas helper T cells and regulatory T cells recognize foreign peptides in association with class II Mhc proteins. In both cases, the T cell recognizes the peptide–Mhc complexes on the surface of an Apc—either a dendritic cell or a target cell. Some regulatory T cells recognize self peptides in association with class II Mhc proteins (not shown).


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Cell_Biology_Alberts. Figure 24–36 Class I and class II MHC proteins. (A) The α chain of the class I molecule has three extracellular domains, α1, α2, and α3, each encoded by a separate exon. The α chain is noncovalently associated with a smaller polypeptide chain, β2-microglobulin, which is not encoded within the Mhc region of the genome. The α3 domain and β2-microglobulin are Ig-like. While β2-microglobulin is invariant, the α chain is extremely polymorphic, mainly in the α1 and α2 domains. (B) In class II Mhc proteins, both the α chain and the β chain are encoded within the Mhc and are polymorphic, mainly in the α1 and β1 domains; the α2 and β2 domains are Ig-like. Thus, there are striking similarities between class I and class II Mhc proteins. In both, the two outermost domains (shaded in blue) are polymorphic and interact to form a groove that binds peptide fragments. (c) The three-dimensional structure of the peptide-binding groove of a human class I Mhc protein is viewed from above, with bound


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Cell_Biology_Alberts. and interact to form a groove that binds peptide fragments. (c) The three-dimensional structure of the peptide-binding groove of a human class I Mhc protein is viewed from above, with bound peptide shown schematically; a peptide must be bound in the groove for the Mhc protein to assemble and be transported to the cell surface. The sides of the groove are formed by two α helices, and the floor is formed by a β pleated sheet. The S–S disulfide bond is shown in red (Movie 24.8 and Movie 24.9). (c, adapted from p.J. Bjorkman et al., Nature 329:506–512, 1987. With permission from Macmillan publishers Ltd.) them have been either eliminated or inactivated, or suppressed by regulatory T cells in the process of self-tolerance. By contrast, in a cell infected by a pathogen such as a virus, the pathogen proteins will be processed in the same way, and peptides derived from them will be displayed on the infected cell surface bound to class I MHC proteins; there, they are recognized by cytotoxic T


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Cell_Biology_Alberts. proteins will be processed in the same way, and peptides derived from them will be displayed on the infected cell surface bound to class I MHC proteins; there, they are recognized by cytotoxic T cells expressing the appropriate TCRs, thereby targeting the infected cell for destruction (Figure 24–38).


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Cell_Biology_Alberts. In general, only antigen-presenting cells (APCs) express class II MHC proteins. Dendritic cells are referred to as professional APCs, as they are specialized for this function and only they can activate naïve T cells. Other immune cells that are targets of effector T cell regulation, including B cells and macrophages, are nonprofessional APCs. All APCs load their newly synthesized class II MHC proteins with peptides derived mainly from extracellular proteins that are endocytosed and delivered to endosomes. The newly synthesized class II MHC proteins initially contain an invariant chain, which occupies the peptide-binding groove


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Cell_Biology_Alberts. Figure 24–37 Human MHC genes. This simplified schematic drawing shows the location of the genes that encode the transmembrane subunits of class I (light green) and class II (dark green) Mhc proteins. The genes shown encode three types of class I Mhc proteins (hLA-A, hLA-B, and hLA-c) and three types of class II Mhc proteins (hLA-Dp, hLA-DQ, and hLA-Dr). An individual can therefore make six types of class I Mhc proteins (three encoded by maternal genes and three by paternal genes) and more than six types of class II Mhc proteins. Because of the extreme polymorphism of the Mhc genes, the chances are very low that the maternal and paternal alleles will be the same. The number of class II Mhc proteins that can be made is greater than six because there are two DR β genes and because maternally encoded and paternally encoded polypeptide chains can sometimes pair. The entire region shown spans about seven million base pairs and contains other genes that are not shown.


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Cell_Biology_Alberts. and prevents it from prematurely binding a peptide until the class II MHC protein reaches specialized vesicles, which fuse with endosomes. Here, the invariant chain is removed and peptide fragments (typically 12–20 amino acids long) produced from endocytosed proteins can bind to the groove of the class II MHC proteins, which are then transported to the plasma membrane for display on the surface of the APC. In a healthy host cell, class II MHC protein grooves are loaded with self-peptides derived from normal proteins and will be ignored by T cells because of self-tolerance mechanisms. During an infection, however, pathogen proteins are also endocytosed and processed in the same way, enabling APCs to present pathogen peptides bound to class II MHC proteins to T cells expressing an appropriate TCR (Figure 24–39).


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Cell_Biology_Alberts. The distinction just discussed between the antigen-processing pathways for loading peptides onto class I and class II MHC proteins is not absolute. Dendritic cells, for example, need to be able to activate cytotoxic T cells to kill virus-infected cells even when the virus does not infect dendritic cells themselves. To do so, specialized subsets of dendritic cells use a process called cross-presentation, which begins when these noninfected dendritic cells phagocytose virus-infected host cells or their fragments. The ingested viral proteins are then released by an unknown mechanism from phagolysosomes into the cytosol, where they are degraded in proteasomes; the resulting protein fragments are then transported into the ER lumen, where they load onto assembling class I MHC proteins. Cross-presentation in dendritic cells is not confined to endocytosed pathogens and their products: it also operates to activate cytotoxic T cells against tumor antigens of cancer cells and the MHC proteins of


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Cell_Biology_Alberts. in dendritic cells is not confined to endocytosed pathogens and their products: it also operates to activate cytotoxic T cells against tumor antigens of cancer cells and the MHC proteins of foreign organ grafts.


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Cell_Biology_Alberts. Figure 24–38 The processing of an extracellular foreign protein for presentation to cytotoxic T cells. An effector cytotoxic T cell kills a virus-infected cell when it recognizes fragments of an internal viral protein bound to class I Mhc proteins on the surface of the infected cell. Not all viruses enter the cell in the way that this enveloped rNA virus does, but fragments of internal viral proteins always follow the pathway shown. Only a small proportion of the viral proteins synthesized in the cytosol are degraded and transported to the cell surface, but this is sufficient to attract an attack by a cytotoxic T cell. Several chaperone proteins in the er lumen aid the folding and assembly of class I Mhc proteins (not shown). The assembly of class I Mhc proteins and their transport to the cell surface require the binding of either a self or foreign peptide (Movie 24.10).


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Cell_Biology_Alberts. Figure 24–39 The processing of an extracellular protein antigen for presentation to a helper T cell. This simplified depiction shows how peptide–class-II-Mhc complexes are formed in endosomes and delivered via vesicles to the cell surface. Viral envelope glycoproteins can also be processed by this pathway for presentation to helper T cells (not shown): these glycoproteins are normally made in the er and transported via the Golgi for insertion into the plasma membrane; although most of these glycoproteins will be incorporated into the envelope of budding viral particles, some will be endocytosed and enter endosomes, from where they can enter the class II Mhc processing pathway. RECOGNITION BY HELPER T CELL DELIVERY OF PEPTIDE– MHC COMPLEX TO PLASMA MEMBRANE FOR RECOGNITION BY HELPER T CELL Golgi apparatus trans Golgi class II MHC protein late endosome early endosome folded protein antigenplasma membrane DENDRITIC OR TARGET CELL LIMITED PROTEOLYSIS OF ANTIGEN AND INVARIANT CHAIN LEAVES


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Cell_Biology_Alberts. Golgi apparatus trans Golgi class II MHC protein late endosome early endosome folded protein antigenplasma membrane DENDRITIC OR TARGET CELL LIMITED PROTEOLYSIS OF ANTIGEN AND INVARIANT CHAIN LEAVES FRAGMENT OF INVARIANT CHAIN IN BINDING GROOVE OF MHC PROTEIN RELEASE OF INVARIANT CHAIN FRAGMENT AND BINDING OF ANTIGEN-DERIVED PEPTIDE INVARIANT CHAIN DIRECTS CLASS II MHC PROTEIN TO LATE ENDOSOME ENDOCYTOSIS AND DELIVERY TO ENDOSOME fragment of invariant chain CYTOSOL antigenic peptide


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Cell_Biology_Alberts. During an infection, only a small fraction of the many thousands of MHC proteins on the surface of an APC or target cell will have pathogen peptides bound to them. This is sufficient, however: fewer than 50 copies of such a peptide–MHC complex on a dendritic cell, for example, can activate a helper T cell that has a TCR that binds the complex with a high-enough affinity. Table 24–3 compares the properties of class I and class II MHC proteins. Mhc proteins Are the Most polymorphic human proteins Known


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Cell_Biology_Alberts. Mhc proteins Are the Most polymorphic human proteins Known Although any individual can make only a small number of different class I and class II MHC proteins, together, these proteins must be able to present peptide fragments from almost any foreign protein to T cells. Thus, unlike the antigen-binding site of an Ig protein, the peptide-binding groove of each MHC protein must be able to bind a very large number of different peptides. The genes encoding class I and class II MHC proteins (see Figure 24–37) are the most polymorphic known in higher vertebrates: in the human population, for example, there are more than 2000 allelic variants of these genes. The corresponding variations in the MHC proteins are concentrated in the floor and walls of the peptide-binding grooves and allow MHC molecules in different individuals to bind different arrays of peptides.


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Cell_Biology_Alberts. It is thought that infectious diseases have been an important driving force for generating this remarkable MHC polymorphism. In the evolutionary war between pathogens and the adaptive immune system, pathogens will tend to change their proteins through mutation so that the peptides derived from them will not fit in the MHC peptide-binding grooves. When a pathogen succeeds, it can sweep through a population as an epidemic. In such circumstances, the few individuals who produce a new allelic form of MHC protein that can bind peptides derived from the altered pathogen will have a large selective advantage. This type of selection will tend to promote and maintain a large diversity of MHC proteins in the population. In West Africa, for example, individuals with a specific MHC allele (HLA-B53) have a reduced susceptibility to a severe form of malaria that is endemic there; although this allele is rare elsewhere, it is found in 25% of the West African population.


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Cell_Biology_Alberts. The extensive diversity of human MHC proteins is the main reason that individuals who receive a foreign organ transplant must be treated with strong immunosuppressive drugs to prevent the immunological rejection of the grafted organ. Of all the foreign proteins that the graft expresses, the MHC proteins are by far the most powerful stimulators of the recipient’s T cells, which would rapidly destroy the graft if they were not prevented from doing so by such drugs. Foreign MHC proteins are powerful T cell stimulants because T cells respond to them in the same way they respond to self MHC proteins that have foreign peptides bound to them; for this reason, the proportion of a person’s T cells that can specifically recognize any foreign MHC protein is relatively high. cD4 and cD8 co-receptors on T cells Bind to Invariant parts of Mhc proteins


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Cell_Biology_Alberts. cD4 and cD8 co-receptors on T cells Bind to Invariant parts of Mhc proteins The affinity of TCRs for peptide–MHC complexes on an APC is usually too low by itself to mediate a functional interaction between the two cells. T cells normally require accessory receptors to help stabilize the interaction by increasing the overall strength of the cell–cell adhesion. Unlike TCRs or MHC proteins, the accessory receptors are invariant and do not bind to foreign peptides. Once bound to the surface of a dendritic cell, for example, a T cell increases the strength of the binding by activating an integrin adhesion protein (discussed in Chapter 19), which then binds more strongly to an Ig-like protein on the surface of the dendritic cell. This increased adhesion enables the T cell to remain bound long enough to become activated.


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Cell_Biology_Alberts. When an accessory receptor has a direct role in activating the T cell by generating its own intracellular signals, it is called a co-receptor. The most important and best understood of the co-receptors on T cells are the CD4 and CD8 proteins, both of which are single-pass transmembrane proteins with extracellular Ig-like domains. Like TCRs, they recognize MHC proteins, but, unlike TCRs, they bind to invariant parts of the MHC protein, far away from the peptide-binding groove. CD4 is expressed on both helper T cells and regulatory T cells and binds to class II MHC proteins, whereas CD8 is expressed on cytotoxic T cells and binds to class I MHC proteins (Figure 24–40).


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Cell_Biology_Alberts. CD4 and CD8 contribute to T cell recognition by helping the T cell to focus on particular MHC proteins, and thereby on particular types of target cells. Thus, the recognition of class I MHC proteins by CD8 allows cytotoxic T cells to focus on any type of infected host cell, while the recognition of class II MHC proteins by CD4 allows helper and regulatory T cells to focus on the target immune cells that they help or suppress, respectively. The cytoplasmic tail of the CD4 and CD8 proteins is associated with a member of the Src family of cytoplasmic tyrosine kinases


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Cell_Biology_Alberts. Figure 24–40 CD4 and CD8 co-receptors on the surface of T cells. cytotoxic T cells (Tc) express cD8, which recognizes class I Mhc proteins, whereas helper T cells (Th) and regulatory T cells (not shown) express cD4, which recognizes class II Mhc proteins. Note that the co-receptors bind to the same Mhc protein that the Tcr has engaged, so that they are brought together with Tcrs during the antigen-recognition process. Whereas the Tcr binds to the variable (polymorphic) parts of the Mhc protein that form the peptide-binding groove, the co-receptor binds to the invariant part, well away from the binding groove. (discussed in Chapter 15) called Lck, which phosphorylates various intracellular proteins on tyrosines and thereby participates in the activation of the T cell (discussed later).


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Cell_Biology_Alberts. (discussed in Chapter 15) called Lck, which phosphorylates various intracellular proteins on tyrosines and thereby participates in the activation of the T cell (discussed later). The AIDS virus (HIV) uses CD4 molecules (as well as chemokine receptors) to enter helper T cells (see Figure 23–17). AIDS patients are susceptible to infection by microbes that are not normally dangerous because HIV depletes helper T cells. As a result, most AIDS patients die of infection within several years of the onset of symptoms, unless they are treated with a combination of anti-HIV drugs. HIV also uses CD4 and chemokine receptors to enter macrophages, which also have both types of receptors on their surface.


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Cell_Biology_Alberts. T cell development begins when bone-marrow-derived lymphoid progenitor cells enter the thymus from the bloodstream. There, the cells receive a variety of signals from thymus stromal cells, epithelial cells, macrophages, and dendritic cells, which promote their stepwise development into mature thymocytes. At one step, the progenitor cells are induced to express V(D)J recombinase and begin to rearrange their TCR gene segments. Soon thereafter, the cells express both CD4 and CD8 co-receptors, and these so-called double‑positive thymocytes migrate inward and interact with thymus dendritic cells or epithelial cells expressing self peptides bound to class I and class II MHC proteins. If the TCR on the thymocyte binds with high affinity to these complexes, a strong signal will be transmitted, causing the cell to undergo apoptosis. This process, called negative selection, is an example of clonal deletion (see Figure 24–21), and it eliminates thymocytes that could potentially attack normal


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Cell_Biology_Alberts. causing the cell to undergo apoptosis. This process, called negative selection, is an example of clonal deletion (see Figure 24–21), and it eliminates thymocytes that could potentially attack normal host cells and tissues and thereby cause an autoimmune disease if the cells were to continue to mature and leave the thymus.


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Cell_Biology_Alberts. If its TCR is unable to bind at all to a self-peptide–MHC complex in the thymus, the thymocyte will fail to receive the signals it needs to survive and will die of “neglect;” without the ability to recognize self-MHC proteins, a T cell would generally be of no use, as T cells can only see pathogen-derived peptides in the context of self-MHC proteins. Thymocytes that express a TCR that binds with an appropriate affinity to a self peptide bound to either a class I MHC protein (using CD8 as a co-receptor) or a class II MHC protein (using CD4 as a co-receptor) will receive an optimal signal to survive and continue to mature, a process called positive selection (Figure 24–41). As part of this maturation process, and depending on the TCR’s preference for class I or class II MHC proteins, the CD4 or CD8 co-receptor that is not needed is silenced by DNA methylation of the respective gene; this results in the development of CD4 or CD8 single‑positive thymocytes, which exit the thymus as naïve


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Cell_Biology_Alberts. or CD8 co-receptor that is not needed is silenced by DNA methylation of the respective gene; this results in the development of CD4 or CD8 single‑positive thymocytes, which exit the thymus as naïve T cells and enter the recirculating pool of T cells—the CD4 cells as either helper or regulatory T cells and the CD8 cells as cytotoxic T cells.


Cell_Biology_Alberts

Cell_Biology_Alberts. Although naïve helper and cytotoxic T cells constantly receive survival signals in the form of self peptides bound to MHC proteins that the T cells bind weakly, a T cell is only activated to proliferate and mount an immune response if its TCR binds with high affinity to a peptide–MHC complex and receives co-stimulatory signals at the same time. Generally, this happens only when the T cell encounters an activated dendritic cell (in a peripheral lymphoid organ) that expresses an MHC protein with a foreign peptide derived from a pathogen in its binding groove. Only then will the naïve T cell proliferate and differentiate into an effector or memory T cell.


Cell_Biology_Alberts

Cell_Biology_Alberts. Negative selection in the thymus is a major mechanism for ensuring that peripheral T cells do not react with host cells expressing MHC proteins with peptides derived from self proteins in their peptide-binding grooves. This mechanism, however, requires that the APCs in the thymus display an array of peptides on their MHC molecules that will reflect the self proteins in peripheral tissues, as well as in the thymus. The thymus, however, would not be expected to produce many of the proteins that are specifically expressed in other organs. As an example, it would not be expected to produce insulin, and yet it is crucial to delete thymocytes with TCRs that could recognize insulin-derived peptides bound to MHC


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Cell_Biology_Alberts. DEATH BY DEFAULT NEGATIVE SELECTION (signaled death) DEATH BY DEFAULT apoptotic cell TH POSITIVE SELECTION (signaled survival) SURVIVAL, MATURATION, and EMIGRATION TH TC TC Treg Treg proteins on the surface of insulin-secreting β cells in the pancreas. Any failure to do so would result in the T-cell-dependent destruction of the β cells and, as a consequence, cause type 1 (or juvenile) diabetes.


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Cell_Biology_Alberts. The mechanism that enables the deletion of all such cells in the thymus depends on a subpopulation of epithelial cells in the thymus that express a transcriptional regulator called AIRE (autoimmune regulator). By a poorly understood mechanism, the AIRE protein promotes the production of small amounts of mRNA from many genes that encode such “organ-specific” proteins, including the insulin gene. When the peptides derived from the proteins encoded by these genes are bound by MHC proteins and displayed on the surface of the epithelial cells in the thymus medulla, this is sufficient to provoke the deletion of the potentially self-reactive thymocytes. Mutations that inactivate the AIRE gene cause a severe multiorgan autoimmune disease in both mice and humans, indicating the importance of AIRE in self-tolerance. cytotoxic T cells Induce Infected Target cells to Kill Themselves


Cell_Biology_Alberts

Cell_Biology_Alberts. Cytotoxic T cells (TC cells), like the NK cells discussed earlier, protect us against intracellular pathogens, including viruses, bacteria, and parasites, that multiply in the cytoplasm of a host cell. TC cells kill infected host cells before the pathogen can escape to infect neighboring host cells. Before it can kill, however, a naïve TC cell has to become an effector cell by activation on an APC, usually an activated dendritic cell that has pathogen-derived peptides bound to class I MHC proteins—a process that depends on helper T cells. The effector TC cell can then recognize any target cell harboring the same pathogen and expressing some of the same peptide–MHC complexes on its surface: its TCRs cluster, along with CD8 co-receptors, adhesion molecules, and intracellular signaling proteins (discussed later), at the interface between the two cells, forming an immunological synapse. In this process, the effector TC cell reorganizes its cytoskeleton to focus its killing apparatus on


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Cell_Biology_Alberts. (discussed later), at the interface between the two cells, forming an immunological synapse. In this process, the effector TC cell reorganizes its cytoskeleton to focus its killing apparatus on the target cell, secreting its toxic proteins into a confined space (Figure 24–42); in this way, it avoids killing neighboring cells. A similar synapse forms when an effector helper T cell interacts with its target cell, except that the co-receptor is CD4 (Movie 24.11).


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Cell_Biology_Alberts. Figure 24–41 Positive and negative selection in the thymus. Developing thymocytes with Tcrs that would potentially enable them to respond to peptides in association with self Mhc proteins after they leave the thymus are positively selected: the binding of their Tcrs to self peptides bound to self Mhc proteins in the thymus signals such cells to survive, mature, and migrate to peripheral lymphoid organs. All of the other thymocytes undergo apoptosis—either because they do not express Tcrs that recognize self Mhc proteins with self peptides bound or because they recognize such complexes too well and undergo negative selection. The regulatory T cells (Treg cells) that are positively selected in the thymus are called natural Treg cells to distinguish them from induced Treg cells, which develop in peripheral lymphoid organs from naive helper T cells (Th cells), as we discuss shortly.


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Cell_Biology_Alberts. Figure 24–42 effector cytotoxic T cells killing target cells in culture. (A) electron micrograph showing an effector cytotoxic T cell (Tc cell) binding to a target cell. The Tc cells were obtained from mice immunized with the target cells, which are foreign tumor cells. (B) electron micrograph showing a Tc cell and a tumor cell that the Tc cell has killed. In an animal, as opposed to a culture dish, the killed target cell would be phagocytosed by neighboring cells (especially macrophages) long before it disintegrated in the way that it has here. (c) Immunofluorescence micrograph of a Tc cell and tumor cell after immunofluorescence staining with anti-tubulin antibodies. Note that the centrosome in the Tc cell is located at the point of cell–cell contact with the target cell—an immunological synapse. The secretory granules (not visible) in the Tc cell are initially transported along microtubules to the centrosome, which then moves to the synapse, delivering the granules to where they


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Cell_Biology_Alberts. synapse. The secretory granules (not visible) in the Tc cell are initially transported along microtubules to the centrosome, which then moves to the synapse, delivering the granules to where they can release their contents. (A and B, from D. Zagury et al., Eur. J. Immunol. 5:818–822, 1975. With permission from John Wiley & Sons, Inc; c, from B. Geiger, D. rosen and G. Berke, J. Cell Biol. 95:137–143, 1982. With permission from the authors.)


Cell_Biology_Alberts

Cell_Biology_Alberts. An effector TC cell (or an NK cell) can employ one of two strategies to kill the target, both of which operate by inducing the target cell to activate caspases and kill itself by undergoing apoptosis. One mechanism uses a protein called Fas ligand on the killer-cell surface, which binds to a transmembrane receptor protein called Fas on the target cell; this mechanism is discussed in Chapter 18 (see Figure 18–5). The other mechanism is the main one used by both NK cells and TC cells to kill an infected target cell. The killer cell stores various toxic proteins within secretory vesicles in its cytoplasm that it releases into the synaptic space by exocytosis. The toxic proteins include perforin and proteases called granzymes. The perforin is homologous to complement component C9 and polymerizes in Figure 24–43 The main way that an the target-cell plasma membrane (see Figure 24–8), forming a transmembrane effector TC cell (or NK cell) kills an pore that disrupts the membrane and allows


Cell_Biology_Alberts

Cell_Biology_Alberts. in Figure 24–43 The main way that an the target-cell plasma membrane (see Figure 24–8), forming a transmembrane effector TC cell (or NK cell) kills an pore that disrupts the membrane and allows the granzymes to enter the target infected target cell. This simplified drawing shows how the killer cell releases cell. Once in the cytosol, the granzymes help activate caspases, thereby inducing perforin and granzymes onto the surface apoptosis (Figure 24–43).


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Cell_Biology_Alberts. of an infected target cell by localized exocytosis at an immunological synapse. The high concentration of ca2+ in the extracellular fluid causes the perforin to assemble into transmembrane channels in the target-cell plasma membrane, allowing the granzymes to enter the target-cell cytosol. The granzymes cleave and activate procaspases to initiate a caspase cascade, leading to apoptosis (see Figure 18–3). A single cytotoxic cell can kill multiple target cells in sequence. It remains a mystery why the released perforins do not form pores in the plasma membrane of the killer cell itself target cell (Movie 24.12 and Movie 24.13). effector helper T cells help Activate Other cells of the Innate and Adaptive Immune Systems


Cell_Biology_Alberts

Cell_Biology_Alberts. In contrast to TC cells, helper T cells (TH cells) are crucial for defense against both extracellular and intracellular pathogens, and they express CD4 rather than CD8 co-receptors and recognize foreign peptides bound to class II rather than class I MHC proteins. Once naïve TH cells are induced on activated dendritic cells to become effector cells, they can help activate other cells: they help activate B cells to become antibody-secreting cells and later to undergo Ig class switching and somatic hypermutation; they help activate macrophages to destroy any intracellular pathogens multiplying within the macrophage’s phagosomes; they help induce naïve TC cells to become effector cells that can kill infected target cells; and they stimulate the activated dendritic cell that activated them to maintain the dendritic cell in an activated state. In each case, the effector TH cell recognizes the same complex of foreign peptide and class II MHC protein on the target-cell surface that it


Cell_Biology_Alberts

Cell_Biology_Alberts. to maintain the dendritic cell in an activated state. In each case, the effector TH cell recognizes the same complex of foreign peptide and class II MHC protein on the target-cell surface that it initially recognized on the activated dendritic cell. As discussed later, the TH cell stimulates the target cell both by secreting a variety of cytokines and by displaying co-stimulatory proteins on its surface.


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Cell_Biology_Alberts. Naïve helper T cells can Differentiate Into Different Types of effector T cells When activated by binding to a foreign peptide bound to a class II MHC protein on an activated dendritic cell, a naïve TH cell can differentiate into several distinct types of effector T cells, depending on the nature of the pathogen and the cytokines they encounter. These cells include four subtypes of helper cells—TH1, TH2, TFH, and TH17 cells—and regulatory (suppressor) T cells. Figure 24–44 summarizes both the cytokines that induce these effector T cells and some of the cytokines the effector cells secrete, as well as the master transcription regulators that control the effector cell’s development. Naïve TH cells activated by dendritic cells secreting the cytokine interleukin-12 (IL12) develop into TH1 cells. These effector cells produce interferon‑γ (IFNγ),


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Cell_Biology_Alberts. Naïve TH cells activated by dendritic cells secreting the cytokine interleukin-12 (IL12) develop into TH1 cells. These effector cells produce interferon‑γ (IFNγ), Figure 24–44 Differentiation of naïve helper T cells into different types of effector helper cells or regulatory T cells in a peripheral lymphoid organ. The cytokines produced by the activating dendritic cell (and by other cells in the environment) mainly determine which type of effector T cell develops, as indicated. Some of the main cytokines produced by each type of effector cell are also shown, and the master transcription regulator for each subset is indicated in the nucleus. There is increasing evidence that some of the effector cells are plastic and can change the cytokines they produce in response to changes in their environment (not shown).


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Cell_Biology_Alberts. which is critical for the activation of macrophages to destroy pathogens that either invaded the macrophage or were ingested by it; the IFNγ can also induce B cells to switch the class of Ig they are making. Naïve TH cells activated in the presence of IL4 develop into TH2 cells. These effector cells are important for the control of extracellular pathogens, including parasites. They stimulate B cells to undergo somatic hypermutation and to switch the class of Ig they produce: for example, the TH2 cells themselves produce IL4, which can induce B cells to switch from making IgM and IgD to making IgE antibodies, which can bind to mast cells, as discussed earlier. Naïve TH cells activated in the presence of IL6 and IL21 develop into follicular helper T cells (TFH), which are located in lymphoid follicles and secrete a variety of cytokines, including IL4 and IL21; these cells are especially important for stimulating B cells to undergo Ig class switching and somatic hyper-mutation. Naïve TH


Cell_Biology_Alberts

Cell_Biology_Alberts. follicles and secrete a variety of cytokines, including IL4 and IL21; these cells are especially important for stimulating B cells to undergo Ig class switching and somatic hyper-mutation. Naïve TH cells activated in the presence of IL6 and TGFβ develop into TH17 cells. These effector cells secrete IL17, which recruits neutrophils and stimulates epithelial cells and fibroblasts in the skin and gut to produce pro-inflammatory cytokines. TH17 cells are important in controlling extracellular bacterial and fungal infections and in wound healing, but they can also have a major role in autoimmune diseases and allergy.


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Cell_Biology_Alberts. In some cases, naïve TH cells that encounter their antigen in a peripheral lymphoid organ in the presence of TGFβ and the absence of IL6 develop into induced regulatory T cells (Treg cells), which suppress rather than help immune cells; as mentioned earlier, natural Treg cells develop in the thymus during thymocyte development (see Figure 24–41). In either case, the Treg cells suppress the development, activation, or function of most other types of immune cells, by means of both secreted suppressive cytokines such as IL10 and TGFβ and inhibitory proteins on the Treg cell surface. Induced Treg cells seem mainly to suppress immune responses to foreign antigens—preventing responses to harmless ingested or inhaled antigens and limiting responses against pathogens to avoid excessive responses that cause unwanted pathology; natural Treg cells are needed to prevent immune responses to self molecules (see Figure 24–21). Treg cells express the transcription regulator FoxP3, which serves as


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Cell_Biology_Alberts. that cause unwanted pathology; natural Treg cells are needed to prevent immune responses to self molecules (see Figure 24–21). Treg cells express the transcription regulator FoxP3, which serves as both a marker of these cells and a master controller of their development: if the gene encoding this protein is inactivated in mice or humans, the individuals fail to produce Treg cells and develop a fatal autoimmune disease involving multiple organs—findings that establish the crucial importance of Treg cells in self-tolerance.


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Cell_Biology_Alberts. Foreign antigen binding to BCRs or TCRs initiates the process whereby the T and B cells are stimulated to proliferate and differentiate into effector or memory cells. As mentioned earlier, these antigen receptors do not act on their own: they are stably associated with invariant transmembrane polypeptide chains that are required to relay the signal into the cell. In B cells, these are called Igα and Igβ (Figure 24–45A), while in T cells they exist in a complex called CD3, composed of four types of polypeptide chains (Figure 24–45B). In both cases, the associated proteins help convert extracellular antigen binding to the TCR or BCR into intracellular signals, and they do so in similar ways.


Cell_Biology_Alberts

Cell_Biology_Alberts. Antigen binding to BCRs or TCRs clusters these receptors and their associated invariant chains (and CD4 or CD8 co-receptors in the case of TCRs). This clustering activates a Src family cytoplasmic tyrosine kinase to phosphorylate tyro-sines on the cytoplasmic tails of some of the invariant chains. The phosphotyrosines then serve as docking sites for a second cytoplasmic tyrosine kinase, which becomes phosphorylated and activated by the first kinase; the second kinase then relays the signal downstream by phosphorylating other intracellular signaling proteins on tyrosines. Some of these early events in the signaling pathway activated by BCRs are shown in Figure 24–46.


Cell_Biology_Alberts

Cell_Biology_Alberts. Signaling through BCRs or TCRs and their associated proteins alone is not sufficient to activate a lymphocyte to proliferate and differentiate. Extracellular co-stimulatory signals produced by another cell are also required, and they are provided by membrane-bound proteins (see Figure 24–34) and secreted cytokines. Indeed, signaling through the BCR or TCR with insufficient co-stimulation can either eliminate the lymphocyte (clonal deletion) or inactivate it, with both of these mechanisms contributing to self-tolerance (see Figure 24–21). For a naïve T cell, an activated dendritic cell provides the co-stimulatory signals; these include the transmembrane B7 proteins, which are recognized by the co-receptor protein CD28 on the surface of the T cell (Figure 24–47A). For a B cell, an effector TH cell provides the co-stimulatory signals; these include the transmembrane CD40 ligand, which binds to CD40 receptors on the B cell (Figure 24–47B). The CD40 ligand on effector TH cells acts in two


Cell_Biology_Alberts

Cell_Biology_Alberts. TH cell provides the co-stimulatory signals; these include the transmembrane CD40 ligand, which binds to CD40 receptors on the B cell (Figure 24–47B). The CD40 ligand on effector TH cells acts in two other situations: (1) it acts back on CD40 receptors on the dendritic cell surface to increase and sustain the activation of the dendritic cell, creating a positive feedback loop; and (2) it acts as a co-stimulatory signal on the surface of an effector TH1 cell, allowing the T cell to help activate an infected macrophage to destroy the pathogens it harbors.


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Cell_Biology_Alberts. In addition to receptors for co-stimulatory proteins, both B and T cells have inhibitory proteins on their surface that help regulate the cell’s activity, preventing excessive or inappropriate responses. Two such proteins expressed by T cells have attracted great attention because of their roles in suppressing the ability of T cells to inhibit cancer progression: CTLA4 and PD1 proteins inhibit T cell activity in different ways, and monoclonal antibodies against either or especially both can relieve the inhibition and allow T cells to dramatically destroy the tumors in some patients with metastatic cancer (see Figure 20–45). Figure 24–45 The invariant chains associated with bCRs and TCRs.


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Cell_Biology_Alberts. Figure 24–45 The invariant chains associated with bCRs and TCRs. (A) each Bcr is associated with two invariant heterodimers, each composed of an Igα and an Igβ polypeptide chain linked by a sulfide bond (red). (B) each Tcr is associated with an invariant cD3 complex composed of two disulfide-bonded ζ chains, two ε chains, and one δ and one γ chain; these chains form homodimers or heterodimers, as shown.


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Cell_Biology_Alberts. Figure 24–46 early signaling events in a b cell activated by the binding of specific foreign antigen to its bCRs. If the antigen is on the surface of a pathogen or is a soluble macromolecule with two or more identical antigenic determinants (as shown), it cross-links adjacent Bcrs, causing them and their associated invariant chains to cluster, as shown. A Src-like cytoplasmic tyrosine kinase (which can be Fyn or Lyn) is associated with the cytosolic tail of Igβ; it joins the cluster and phosphorylates both the Igα and Igβ invariant chains (for simplicity, only the phosphorylation on Igβ is shown). A transmembrane protein tyrosine phosphatase called CD45 is also required to remove inactivating phosphates from these Src-like kinases (not shown). The resulting phosphotyrosines on Igα and Igβ serve as docking sites for another Src-like tyrosine kinase called Syk, which becomes phosphorylated and thereby activated to relay the signal downstream.


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Cell_Biology_Alberts. The pathway from Tcrs is similar (including a requirement for cD45), except that the first Src-like kinase is Lck, which is associated with a cD4 or cD8 co-receptor and phosphorylates tyrosines on all the cD3 polypeptide chains shown in Figure 24–45B; the second Src-like kinase is ZAP70, which is homologous to the Syk kinase in B cells (Movie 24.14). Many cell-Surface proteins Belong to the Ig Superfamily


Cell_Biology_Alberts

Cell_Biology_Alberts. Many cell-Surface proteins Belong to the Ig Superfamily Most of the proteins that mediate antigen recognition and cell–cell recognition in the immune system contain one or more Ig or Ig-like domains, suggesting that the proteins have a common evolutionary history. Included in this very large Ig superfamily are antibodies, TCRs, MHC proteins, the CD4, CD8, and CD28 co-receptors, the B7 co-stimulatory proteins, and most of the invariant polypeptide chains associated with TCRs and BCRs, as well as the various Fc receptors on lymphocytes and other leukocytes. Many of these proteins are dimers or higher oligomers, in which Ig or Ig-like domains of one chain interact with those in another (Figure 24–48).


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Cell_Biology_Alberts. Figure 24–47 Comparison of the co-stimulatory proteins required to activate a helper T cell and a b cell in response to the same foreign protein. (A) A naïve helper T cell is activated by a peptide fragment of a foreign protein bound to a class II Mhc protein on the surface of an activated dendritic cell. The co-stimulatory protein on the dendritic cell (a B7 protein— either cD80 or cD86) binds to the cD28 co-receptor on the T cell, providing a necessary co-stimulatory signal to the T cell; in addition, cytokines secreted by the dendritic cell (or other nearby cells) influence what subtype of effector helper cell the T cell becomes (see Figure 24–44). (B) Once activated to become an effector cell, the helper T cell can help activate B cells that have the same peptide–Mhc protein complexes on their surface as the dendritic cell that activated the T cell. These B cells have Bcrs that bind an antigenic determinant on the surface of a folded foreign protein and endocytose the protein


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Cell_Biology_Alberts. on their surface as the dendritic cell that activated the T cell. These B cells have Bcrs that bind an antigenic determinant on the surface of a folded foreign protein and endocytose the protein (red arrow); the protein is then cleaved into peptides, which are carried to the B cell surface by class II Mhc proteins, where some of them can be recognized by the Tcrs on the helper T cell (see Figure 24–39). Note that the Bcrs and Tcrs recognize different antigenic determinants of the protein. As indicated, the co-stimulatory protein used by the effector helper T cell is cD40 ligand, which binds to the cD40 co-receptor on the B cell; the T cell also secretes cytokines such as IL4 to help stimulate the B cell to undergo somatic hypermutation and class switching (not shown). The cD4 co-receptor on Th cells is omitted in both (A) and (B) for simplicity.


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Cell_Biology_Alberts. Figure 24–48 Some of the cell-surface proteins discussed in this chapter that belong to the Ig superfamily. The Ig and Ig-like domains are shaded in gray, except for the antigen-binding domains (not all of which are Ig domains—the class I and class II Mhc proteins are the exception), which are shaded in blue. The Ig superfamily also includes many cell-surface proteins involved in cell–cell interactions outside the immune system, such as the neural cell adhesion molecule (N-cAM) discussed in chapter 19 and the receptors for various protein growth factors discussed in chapter 15 (not shown). There are more than 750 members of the Ig superfamily in humans.


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Cell_Biology_Alberts. In both vertebrates and invertebrates, many proteins in the Ig superfamily are also found outside immune systems, where they often function in cell–cell recognition and adhesion processes, both during development and in adult tissues. It seems likely that the entire gene superfamily evolved from a primordial gene coding for a single Ig-like domain, similar to that encoding β2-microglobulin (see Figure 24–36). In present-day family members, a separate exon usually encodes the amino acids in each Ig-like domain, consistent with the likelihood that new family members arose during evolution by exon and gene duplications.


Cell_Biology_Alberts

Cell_Biology_Alberts. There are three main functionally distinct classes of T cells. Cytotoxic T cells (TC cells) directly kill infected cells by secreting perforins and granzymes that induce the infected cells to undergo apoptosis. Helper T cells (TH cells) help activate cytotoxic T cells to kill their target cells, B cells to make antibody responses, macrophages to destroy the microorganisms they harbor, and dendritic cells to activate T cells. Regulatory T cells (Treg cells) produce suppressive proteins (such as the cytokines IL10 and TGFβ) to inhibit other immune cells.


Cell_Biology_Alberts

Cell_Biology_Alberts. All T cells express cell‑surface antigen receptors (TCRs), which are encoded by genes that are assembled from multiple gene segments during T cell development in the thymus. TCRs recognize peptide fragments of foreign proteins that are displayed in association with MHC proteins on the surface of antigen‑presenting cells (APCs) and target cells. Naïve T cells are activated in peripheral lymphoid organs by activated dendritic cells, which secrete cytokines and express peptide–MHC complexes, co‑stimulatory proteins, and various cell–cell adhesion molecules on their cell surface.


Cell_Biology_Alberts

Cell_Biology_Alberts. Class I MHC proteins present foreign peptides to TC cells, whereas class II MHC proteins present foreign peptides to TH cells and Treg cells. Whereas class I MHC proteins are expressed on almost all nucleated vertebrate cells, class II MHC proteins are normally restricted to APCs, including dendritic cells, macrophages, and B lymphocytes. Both classes of MHC proteins have a single peptide‑binding groove, which binds a large set of small peptide fragments produced intracellularly by normal protein‑degradation processes: class I MHC proteins mainly bind fragments produced in the cytosol, whereas class II MHC proteins mainly bind fragments produced in endocytic compartments. The peptide–MHC complexes are transported to the cell surface, where complexes that contain a peptide derived from a foreign protein are recognized by TCRs, which interact with both the peptide and the walls of the peptide‑binding groove. T cells also express CD4 or CD8 co‑receptors, which recognize invariant regions


Cell_Biology_Alberts

Cell_Biology_Alberts. protein are recognized by TCRs, which interact with both the peptide and the walls of the peptide‑binding groove. T cells also express CD4 or CD8 co‑receptors, which recognize invariant regions of MHC proteins: TH cells and Treg cells express CD4, which recognizes class II MHC proteins; TC cells express CD8, which recognizes class I MHC proteins.


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Cell_Biology_Alberts. A combination of positive and negative selection operates during T cell development in the thymus to help ensure that only T cells with potentially useful TCRs survive, mature, and emigrate, while all of the others die by apoptosis. The naïve TH and TC cells that leave the thymus constantly receive survival signals when their TCRs recognize self‑peptide–MHC complexes, but they can only be activated when their TCRs encounter foreign peptides in the grooves of MHC proteins on an activated dendritic cell. The natural Treg cells that leave the thymus suppress self‑reactive lymphocytes to help maintain self‑tolerance.


Cell_Biology_Alberts

Cell_Biology_Alberts. The production of an effector T cell from a naïve T cell requires multiple signals from an activated dendritic cell. MHC–peptide complexes on the dendritic cell surface provide one signal, by binding to both TCRs and a CD4 co‑receptor on a TH or Treg cell. Co‑stimulatory proteins on the dendritic cell surface and secreted cytokines are the other signals. When naïve TH cells are initially activated on a dendritic cell, they differentiate into TH1, TH2, TFH, or TH17 effector helper cells or into induced Treg cells, depending mainly on the cytokines in their environment. TH1 cells secrete interferon‑γ (IFNγ) to activate macrophages and to induce B cells to switch the class of Ig they make; TH2 and TFH cells secrete other cytokines that also induce B cells to switch Ig class; and TH17 cells secrete IL17 to promote inflammatory responses What initiates an autoimmune disease such as type 1 diabetes or multiple sclerosis?


Cell_Biology_Alberts

Cell_Biology_Alberts. What initiates an autoimmune disease such as type 1 diabetes or multiple sclerosis? When a naïve or memory T or B cell is activated by antigen and co-stimulatory signals, how does it decide whether to become an effector cell or memory cell? Are there cells that are pre-committed to becoming either effector or memory cells, for example, or is the decision determined solely by extracellular signals? Why do some of us make Ige antibodies against harmless antigens and thereby develop hay fever and allergic asthma, while most of us do not, and why is the proportion of such allergic individuals increasing? how does a cytotoxic T cell (or NK cell) avoid being killed by the perforin and granzymes that it secretes to kill a target cell?


Cell_Biology_Alberts

Cell_Biology_Alberts. how does a cytotoxic T cell (or NK cell) avoid being killed by the perforin and granzymes that it secretes to kill a target cell? and wound healing. The effector helper TH cells recognize the same complex of foreign peptide and class II MHC protein on the target‑cell surface as they initially recognized on the dendritic cell that activated them. They activate their target cells by producing a combination of membrane‑bound and secreted co‑stimulatory proteins. Treg cells suppress immune cells using cell‑surface and secreted inhibitory proteins. Both T cells and B cells require multiple signals for activation. Antigen binding to the TCRs or BCRs provides one signal, while co‑stimulatory proteins binding to co‑receptors and cytokines binding to their complementary receptors provide the others. Effector TH cells provide the co‑stimulatory signals for B cells, whereas APCs provide them for T cells. Which statements are true? explain why or why not.


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Cell_Biology_Alberts. Which statements are true? explain why or why not. 24–1 T cells whose receptors strongly bind a self-peptide–MHC complex are killed off in peripheral lymphoid organs when they encounter the self peptide on an antigen-presenting dendritic cell. 24–2 To guarantee that the antigen-presenting cells in the thymus will display a complete repertoire of self peptides to allow elimination of self-reactive T cells, the thymus recruits dendritic cells from all over the body. 24–3 The antibody diversity created by the combinatorial joining of V, D, and J segments by V(D)J recombination pales in comparison to the enormous diversity created by the random gain and loss of nucleotides at V, D, and J joining sites. Discuss the following problems. 24–4 Why do living trees not rot? Redwood trees, for example, can live for centuries, but once they die they decay fairly quickly. What might this suggest?


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Cell_Biology_Alberts. Discuss the following problems. 24–4 Why do living trees not rot? Redwood trees, for example, can live for centuries, but once they die they decay fairly quickly. What might this suggest? 24–5 It would be disastrous if a complement attack were not confined to the surface of the pathogen that is the target of the attack. Yet, the proteolytic cascade involved in the attack liberates biologically active molecules at several steps: one that diffuses away and one that remains bound to the target surface. How does the complement reaction remain localized when active products leave the surface?


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Cell_Biology_Alberts. [Hint: imagine what would happen if the G:U mismatch created by AID was replicated several times; how would the sequences of the final mutations relate to the original G-C base pair?] 24–7 For many years it was a complete mystery how cytotoxic T cells could see a viral protein that seemed to be present only in the nucleus of the virus-infected cell. The answer was revealed in a classic paper that took advantage of a clone of T cells whose T cell receptor was directed against an antigen assoicated with the nuclear protein of the 1968 strain of influenza virus. The authors of the paper found that when they incubated high concentrations of certain peptides derived from the viral nuclear protein, the cells became sensitive to lysis by subsequent incubation with the cytotoxic T cells. Using various peptides from the 1968 strain and the 1934 strain (with which the cytotoxic T cells did not react), the authors defined the particular peptide responsible for the T cell response (Figure Q24–1).


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Cell_Biology_Alberts. A. Which part of the viral protein gives rise to the peptide that is recognized by the clone of cytotoxic T cells? 24–6 Based on its sequence similarity to Apobec1, which deaminates Cs to Us in RNA, activation-induced deaminase (AID) was originally proposed to work on RNA. But definitive experiments in E. coli demonstrated that AID deaminates Cs to Us in DNA. The authors of the paper expressed AID in bacteria and followed mutations in a selectable gene. They found that AID expression increased mutations about fivefold above the background level in the absence of AID expression. More importantly, they found that 80% of the induced mutations were G→A or C→T. Does this fit with your expectation if AID-induced mutations arose by deamination of C to U in the DNA?


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Cell_Biology_Alberts. Figure Q24–1 Viral nuclear protein recognition by cytotoxic T cells (problem 24–7). (A) Sequences of a segment of the nuclear protein from the 1968 and 1934 strains of influenza virus. peptides used in the experiments in (B) are highlighted by pink bars. The amino acid differences between the viral proteins are highlighted in blue. (B) cytotoxic T-cell-mediated lysis of target cells. The target cells were untreated (none), infected with virus (1968 or 1934 strain), or preincubated with high concentrations of the indicated viral peptide. Why do not all viral peptides sensitize the target cells for lysis by the cytotoxic T cells? b. It is thought the MHC molecules come to the cell surface with peptides already bound. If that is so, how do you imagine that these experiments worked?


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Cell_Biology_Alberts. b. It is thought the MHC molecules come to the cell surface with peptides already bound. If that is so, how do you imagine that these experiments worked? 24–8 Working out the rules by which T cells interact with their target cells was complicated. Some of the key observations came from studying the way cytotoxic T cells killed cells infected with choriomeningitis virus (LCMV). (A) Figure Q24–3 Scanning of the T cell repertoire by dendritic cells (problem 24–9). (A) contacts between different T cells and one dendritic cell. T cells are green and dendritic cells are red. The dendritic cell labeled with of images. Times are shown At first glance, it would seem a dangerous strategy ing the same k-type MHC protein, but they did not lyse as hours: minutes. (B) plot of T cell contacts for individual dendritic cells over time. (A, from p Bousso and proteins (Figure Q24–2). Similarly, cytotoxic T cells from e. robey, Nat. Immunol.


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Cell_Biology_Alberts. (A, from p Bousso and proteins (Figure Q24–2). Similarly, cytotoxic T cells from e. robey, Nat. Immunol. 4:579–581, 2003. With permission from Macmillan d-type mice lysed infected d-type cells, but not infected minutes publishers Ltd.) k-type cells. LCMV can kill both k-type and d-type mice. cytotoxic fbroblasts T cells added to Figure Q24–2 pattern of killing of LcMV-infected fibroblasts by cytotoxic T cells from an LcMV-infected k-type mouse (problem 24–8). A. If homozygous d-type mice were bred to homozygous k-type mice to generate d-type/k-type heterozygous progeny, would you expect that cytotoxic T cells from these heterozygotes, when infected with LCMV, to be able to lyse infected d-type cells? How about infected k-type cells? Explain your answers.


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Cell_Biology_Alberts. b. Oddly enough, LCMV infection does not kill mice that lack a thymus—such as “nude” mice, so called because they also lack hair. If a thymus is transplanted back into a nude mouse, it will die when infected with LCMV. Suppose that a d-type/k-type heterozygous nude mouse was given a thymus from an d-type donor. Would you expect its cytotoxic T cells to be able to lyse infected d-type cells? How about infected k-type cells? Explain your answers.


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Cell_Biology_Alberts. 24–9 Before exposure to a foreign antigen, T cells with receptors specific for the antigen are a tiny fraction of the T cells—on the order of 1 in 105 or 1 in 106 T cells. After exposure to the antigen, only a small number of dendritic cells typically display the antigen on their surface. How long does it take for such antigen-presenting dendritic cells to interact with the antigen-specific T cells, which is the key first step in T cell activation and clonal expansion? The dynamics of the search process were examined by labeling dendritic cells red and T cells green, so that contacts in an for the thymus to actively promote the survival, matura tion, and emigration of developing T cells that bind weakly to self peptides bound to self MHC molecules. Would it not be safer to get rid of these T cells, along with those that bind strongly to such self-peptide–MHC complexes, as this would seem a more secure way to avoid autoimmune reactions?


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Cell_Biology_Alberts. 24–11 CD4 proteins on helper and regulatory T cells serve as co-receptors that bind to invariant parts of class II MHC proteins. CD4 is thought to increase the adhesion between T cells and antigen-presenting cells (APCs) that are initially connected only weakly by the T cell receptor bound to its specific peptide–MHC complex. To test this possibility, you label cell-surface MHC molecules with a fluorescently labeled peptide so that you can detect individual peptide–MHC complexes at the interface between the APCs and the T cells in a culture dish. To detect T cell responses—the sign of a productive contact—you load them with a Ca2+ indicator dye, as cytosolic Ca2+ increases when lymphocytes are active. You now count the peptide– MHC complexes at a large number of interfaces (immunological synapses) and measure the resulting uptake of Ca2+ in the adherent T cells (Figure Q24–4, red circles). When you repeat the experiment in the presence of blocking antibodies against CD4, you get a


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Cell_Biology_Alberts. synapses) and measure the resulting uptake of Ca2+ in the adherent T cells (Figure Q24–4, red circles). When you repeat the experiment in the presence of blocking antibodies against CD4, you get a different result (blue circles). Do these results support or refute the notion that CD4 augments T cell receptor binding? Explain your answer.


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Cell_Biology_Alberts. Figure Q24–4 role of cD4 in the T cell response (problem 24–11). The uptake of ca2+ in cells with different numbers of fluorescently complexes at the interface between the T cells and the ton fluorescence microscopy (Figure Q24–3A). The fre quency of contacts between dendritic cells and T cells antigen-presenting cells. The results in the absence from such experiments is given in Figure 24–3B. Assuming are shown by the red curve; that 100 dendritic cells present the specific antigen, how long would it take them to scan 105 T cells? How long for results in the presence of 0 20406080 cD4 antibodies are shown 106 T cells? number of peptide–MHC complexes by the blue curve. Murphy K (2011) Janeway’s Immunobiology, 8th ed. new York: Garland Science. Abbas AK, Lichtman AH & Pillai S (2014) cellular and Molecular Immunology, 8th ed. Philadelphia: WB Saunders. Parham P (2015) The Immune System, 4th ed. new York: Garland Science. The Innate Immune System


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Cell_Biology_Alberts. Parham P (2015) The Immune System, 4th ed. new York: Garland Science. The Innate Immune System Beutler B & Rietschel eT (2003) Innate immune sensing and its roots: the story of endotoxin. Nat. Rev. Immunol. 3, 169–176. Davis BK, Wen H & Ting JP (2011) The inflammasome nLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29, 707–735. Gallo RL & Hooper LV (2012) epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12, 503–516. Hoffmann J & Akira S (2013) Innate immunity. Curr. Opin. Immunol. 25, 1–3. Holers VM (2014) complement and its receptors: new insights into human disease. Annu. Rev. Immunol. 32, 433–459. Ivashkiv LB & Donlin LT (2014) Regulation of type 1 interferon responses. Nat. Rev. Immunol. 14, 36–49. Janeway cA Jr & Medzhitov R (2002) Innate immune recognition. Annu. Rev. Immunol. 20, 197–216. Kumar H, Kawai T & Akira S (2011) Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34.


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Cell_Biology_Alberts. Kumar H, Kawai T & Akira S (2011) Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34. Lannier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 9, 495–502. Murray PJ & Wynn TA (2011) Protective and pathogenic functions of macrophages. Nat. Rev. Immunol. 11, 723–737. Pluddemann A, Mukhopadhyay S & Gordon S (2011) Innate immunity to intracellular pathogens: macrophage receptors and responses to microbial entry. Immunol. Rev. 240, 11–24. Schenten D & Medzhitov R (2011) The control of adaptive immune responses by the innate immune system. Adv. Immunol. 109, 87–124. Overview of the Adaptive Immune System Denucci cc, Mitchell JS & Shimizu Y (2009) Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit. Rev. Immunol. 29, 87–109.


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Cell_Biology_Alberts. Denucci cc, Mitchell JS & Shimizu Y (2009) Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there. Crit. Rev. Immunol. 29, 87–109. Girard J-P, Moussion c & förster R (2012) HeVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat. Rev. Immunol. 12, 762–773. Klein L, Yudanin nA & Restifo nP (2013) Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35. MacKeod MK, Kappler JW & Marrack P (2010) cD4 memory T cells: generation, reactivation, and reassignment. Immunol. 130, 10–15. McHeyzer-Williams M, Okitsu S, Wang n & McHeyzer-Williams L (2011) Molecular programming of B cell memory. Nat. Rev. Immunol. 12, 24–34. Rothenburg eV (2014) Transcriptional control of early T and B cell developmental choices. Annu. Rev. Immunol. 32, 283–321. Schwartz RH (2012) Historical overview of immunological tolerance. Cold Spr. Harb. Perspect. Biol. 4, 1–14.


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Cell_Biology_Alberts. Schwartz RH (2012) Historical overview of immunological tolerance. Cold Spr. Harb. Perspect. Biol. 4, 1–14. Sprent J & Surh cD (2011) normal T cell homeostasis: the conversion of naïve cells into memory-phenotype cells. Nat. Immunol. 12, 478–484. eibel H, Kraus H, Sic H et al. (2014) B cell biology: an overview. Curr. Allergy Asthma Rep. 14, 434–444. Ganesh K & neuberger MS (2011) The relationship between hypothesis and experiment in unveiling the mechanisms of antibody gene diversification. FASEB J. 25, 1123–1132. Kurosaki T, Shinohara H, & Baba Y (2010) B cell signalling and fate decision. Annu. Rev. Immunol. 29, 21–55. nimmerjahn f & Ravetch JV (2007) fc-receptors as regulators of immunity. Adv. Immunol. 96, 179–204. Schatz DG & Yanhong J (2010) Recombination centers and the orchestration of V(D)J recombination. Nat. Rev. Immunol. 11, 251–263. Schomchik MJ & Weisel f (2012) Germinal center selection and development of memory B and plasma cells. Immunol. Rev. 247, 52–63.


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Cell_Biology_Alberts. Schomchik MJ & Weisel f (2012) Germinal center selection and development of memory B and plasma cells. Immunol. Rev. 247, 52–63. Schroeder HW & cavacini L (2010) Structure and function of immunoglobulins. J. Aller. Clin. Immunol. 125, S41–S52. Xu Z, Zan H, Pone eJ et al. (2012) Immunoglobulin class-switch DnA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12, 517–531. T Cells and the MHC Bjorkman PJ (2006) finding the groove. Nat. Immunol. 7, 787–789. Blum JS, Wearsch PA & cresswell P (2013) Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473. clambey eT, Davenport B, Kappler JW et al. (2014) Molecules in medicine mini review: the αβ T cell receptor. J. Mol. Med. 92, 735–741. Dustin ML (2014) What counts in the immunological synapse. Mol. Cell 54, 255–262. ewen cL, Kane KP & Bleackley Rc (2012) A quarter century of granzyme. Cell Death Differ. 19, 28–35.


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Cell_Biology_Alberts. Dustin ML (2014) What counts in the immunological synapse. Mol. Cell 54, 255–262. ewen cL, Kane KP & Bleackley Rc (2012) A quarter century of granzyme. Cell Death Differ. 19, 28–35. Hniffa M, collin M & Ginhoux f (2013) Ontogeny and functional specialization of dendritic cells in human and mouse. Adv. Immunol. 120, 1–49. Harwood ne & Batista fD (2010) early events in B cell activation. Annu. Rev. Immunol. 28, 185–210. Hsieh cS, Lee HM & Lio cW (2012) Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 10, 157–167. Huppa JB & Davis MM (2013) The interdisciplinary science of T-cell recognition. Adv. Immunol. 119, 1–50. Joffre OP, Segura e, Savina A & Amigorena S (2012) cross-presentation by dendritic cells. Nat. Rev. Immunol. 12, 557–569. Josefowicz SZ, Lu L-f & Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564.


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Cell_Biology_Alberts. Josefowicz SZ, Lu L-f & Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564. Klein L, Kyewski B, Allen PM & Hogquist KA (2014) Positive and negative selection of the T cell repertoire: what the thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391. Liu K & nussenzweig Mc (2010) Origin and development of dendritic cells. Immunol. Rev. 234, 45–54. Mathis D & Benoist c (2009) AIRe. Annu. Rev. Immunol. 27, 287–312. McDevitt HO (2000) Discovering the role of the major histocompatibility complex in the immune response. Annu. Rev. Immunol. 18, 1–17. Ohkura n, Kitagawa Y & Sakagucci S (2013) Development and maintenance of regulatory T cells. Semin. Immunol. 23, 424–430. Ramsdell f & Ziegler Sf (2014) fox3P and scurfy: how it all began. Nat. Rev. Immunol. 14, 343–349. Rudolph MG, Stanfield RL & Wilson IA (2006) How TcRs bind MHcs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466.


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Cell_Biology_Alberts. Rudolph MG, Stanfield RL & Wilson IA (2006) How TcRs bind MHcs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466. Schuette V & Burgdorf S (2014) The ins-and-outs of endosomal antigens for cross presentation. Curr. Opin. Immunol. 26, 63–68. Shevach eM (2011) Biological functions of regulatory T cells. Adv. Immunol. 112, 137–176. Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22. Trombetta eS & Mellman I (2005) cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028. Zhu J, Yamane H & Paul We (2010) Peripheral cD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Annu. Rev. Immunol. 28, 445–489.


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Cell_Biology_Alberts. Zhu J, Yamane H & Paul We (2010) Peripheral cD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Annu. Rev. Immunol. 28, 445–489. ABC transporters A large family of membrane transport proteins that use the energy of ATP hydrolysis to transfer peptides or small molecules across membranes. (Figure 11–16) acetyl CoA Small water-soluble activated carrier molecule. Consists of an acetyl group linked to coenzyme A (CoA) by an easily hydrolyzable thioester bond. (Figure 2–38) acetylcholine receptor (AChR) Membrane protein that responds to binding of acetylcholine (ACh). The nicotinic AChR is a transmitter-gated ion channel that opens in response to ACh. The muscarinic AChR is not an ion channel, but a G-protein-coupled cell-surface receptor.


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Cell_Biology_Alberts. acid A proton donor. Substance that releases protons (H+) when dissolved in water, forming hydronium ions (H3O+) and lowering the pH. (Panel 2–2, pp. 92–93) acid hydrolases Hydrolytic enzymes—including proteases, nucleases, glycosidases, lipases, phospholipases, phosphatases, and sulfatases—that work best at acidic pH; these enzymes are found within the lysosome.


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Cell_Biology_Alberts. action potential Rapid, transient, self-propagating electrical excitation in the plasma membrane of a cell such as a neuron or muscle cell. Action potentials, or nerve impulses, make possible long-distance signaling in the nervous system. (Figure 11–31) activated carrier Small diffusible molecule that stores easily exchangeable energy in the form of one or more energy-rich covalent bonds. Examples are ATP, acetyl CoA, FADH2, NADH, and NADPH. (Figure 2–31) activation energy The extra energy that must be acquired by atoms or molecules in addition to their ground-state energy in order to reach the transition state required for them to undergo a particular chemical reaction. (Figure 2–21) activation-induced deaminase (AID) The enzyme catalyzing the processes of somatic hypermutation and immunoglobulin class switching in activated B cells.


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Cell_Biology_Alberts. active site Region of an enzyme surface to which a substrate molecule binds in order to undergo a catalyzed reaction. (Figure 1–7) active transport Movement of a molecule across a membrane or other barrier driven by energy other than that stored in the electrochemical or concentration gradient of the transported molecule. adaptation (1) Adaptation (desensitization): adjustment of sensitivity following repeated stimulation. The mechanism that allows a cell to react to small changes in stimuli even against a high background level of stimulation. (2) Evolutionary adaptation: an evolved trait.


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Cell_Biology_Alberts. adaptive immune system System of lymphocytes providing highly specific and long-lasting defense against pathogens in vertebrates. It consists of two major classes of lymphocytes: B lymphocytes (B cells), which secrete antibodies that bind specifically to the pathogen or its products, and T lymphocytes (T cells), which can either directly kill cells infected with the pathogen or produce secreted or cell-surface signal proteins that stimulate other host cells to help eliminate the pathogen. (Figure 24–2) adaptor protein, adaptor General term for a protein that functions solely to link two or more different proteins together in an intracellular signaling pathway or protein complex. (Figure 15–11) adenylyl cyclase (adenylate cyclase) Membrane-bound enzyme that catalyzes the formation of cyclic AMP from ATP. An important component of some intracellular signaling pathways.


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Cell_Biology_Alberts. adherens junction Cell junction in which the cytoplasmic face of the plasma membrane is attached to actin filaments. Examples include adhesion belts linking adjacent epithelial cells and focal contacts on the lower surface of cultured fibroblasts. adhesins Specific proteins or protein complexes of pathogenic bacteria that recognize and bind cell-surface molecules on the host cells to enable tight adhesion and colonization of tissues. adhesion belt Adherens junctions in epithelia that form a continuous belt (zonula adherens) just beneath the apical face of the epithelium, encircling each of the interacting cells in the sheet.


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Cell_Biology_Alberts. adhesion belt Adherens junctions in epithelia that form a continuous belt (zonula adherens) just beneath the apical face of the epithelium, encircling each of the interacting cells in the sheet. ADP (adenosine 5′-diphosphate) Nucleotide produced by hydrolysis of the terminal phosphate of ATP. Regenerates ATP when phosphorylated by an energy-generating process such as oxidative phosphorylation. (Figure 2–33) aerobic respiration Process by which a cell obtains energy from sugars or other organic molecules by allowing their carbon and hydrogen atoms to combine with the oxygen in air to produce CO2 and H2O, respectively. affinity maturation Progressive increase in the affinity of antibodies for the immunizing antigen with the passage of time after immunization. Agrin Signal protein released by an axonal growth cone during formation of the synapse between it and a muscle cell.


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Cell_Biology_Alberts. Agrin Signal protein released by an axonal growth cone during formation of the synapse between it and a muscle cell. AIRE (autoimmune regulator) A protein expressed by a subpopulation of epithelial cells in the thymus that stimulates the production of small amounts of self proteins characteristic of other organs, exposing developing thymocytes to these proteins for the purpose of self-tolerance. Akt Serine/threonine protein kinase that acts in the PI-3kinase/Akt intracellular signaling pathway involved especially in signaling cells to grow and survive. Also called protein kinase B (PKB). allele One of several alternative forms of a gene. In a diploid cell, each gene will typically have two alleles, occupying the corresponding position (locus) on homologous chromosomes.


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Cell_Biology_Alberts. allele One of several alternative forms of a gene. In a diploid cell, each gene will typically have two alleles, occupying the corresponding position (locus) on homologous chromosomes. allosteric protein A protein that can adopt at least two distinct conformations, and for which the binding of a ligand at one site causes a conformational change that alters the activity of the protein at a second site; this allows one type of molecule in a cell to alter the fate of a molecule of another type, a feature widely exploited in enzyme regulation.


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Cell_Biology_Alberts. allostery (adjective allosteric) Change in a protein’s conformation brought about by the binding of a regulatory ligand (at a site other than the protein’s catalytic site), or by covalent modification. The change in conformation alters the activity of the protein and can form the basis of directed movement. (Figures 3–57 and 16–29) alpha helix (α helix) Common folding pattern in proteins, in which a linear sequence of amino acids folds into a right-handed helix stabilized by internal hydrogen-bonding between backbone atoms. (Figure 3–7) alternative RNA splicing Production of different RNAs from the same gene by splicing the transcript in different ways. (Figure 7–57) amino acid Organic molecule containing both an amino group and a carboxyl group. Those that serve as building blocks of proteins are alpha amino acids, having both the amino and carboxyl groups linked to the same carbon atom. (NH2CHRCOOH, Panel 3–1, pp. 112–113) aminoacyl-tRNA synthetase Enzyme that attaches the correct


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Cell_Biology_Alberts. are alpha amino acids, having both the amino and carboxyl groups linked to the same carbon atom. (NH2CHRCOOH, Panel 3–1, pp. 112–113) aminoacyl-tRNA synthetase Enzyme that attaches the correct amino acid to a tRNA molecule to form an aminoacyltRNA. (Figure 6–54)


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Cell_Biology_Alberts. AMPA receptor Glutamate-gated ion channel in the mammalian central nervous system that carries most of the depolarizing current responsible for excitatory postsynaptic potentials. amphiphilic Having both hydrophobic and hydrophilic regions, as in a phospholipid or a detergent molecule. amyloid fibrils Self-propagating, stable β-sheet aggregates built from hundreds of identical polypeptide chains that become layered one over the other to create a continuous stack of β sheets. The unbranched fibrous structure can contribute to human diseases when not controlled. anaphase (1) Stage of mitosis during which sister chromatids separate and move away from each other. (2) Anaphase I and II: stages of meiosis during which chromosome homolog pairs separate (I), and then sister chromatids separate (II). (Panel 17–1, pp. 980–981) anaphase A Stage of mitosis during which chromosome segregation occurs as chromosomes move toward the two spindle poles.


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Cell_Biology_Alberts. anaphase B Stage of mitosis during which chromosome segregation occurs as spindle poles separate and move apart. anaphase-promoting complex (APC/C; cyclosome) Ubiquitin ligase that catalyzes the ubiquitylation and destruction of securin and Mand S-cyclins, initiating the separation of sister chromatids in the metaphase-to-anaphase transition during mitosis. anchorage dependence Dependence of cell growth, proliferation, and survival on attachment to a substratum. anchoring junction Cell junction that attaches cells to neighboring cells or to the extracellular matrix. (Table 19–1, p. 1037) angiogenesis Growth of new blood vessels by sprouting from existing ones. antenna complex Part of a photosystem that captures light energy and channels it into the photochemical reaction center. It consists of protein complexes that bind large numbers of chlorophyll molecules and other pigments.


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Cell_Biology_Alberts. Antennapedia complex One of two gene clusters in Drosophila that contain Hox genes; genes in the Antennapedia complex control the differences among the thoracic and head segments of the body. anti-apoptotic Bcl2 family proteins Proteins (e.g., Bcl2, BclXL) on the cytosolic surface of the outer mitochondrial membrane that bind and inhibit pro-apoptotic Bcl2 family proteins and thereby help prevent inappropriate activation of the intrinsic pathway of apoptosis. anti-IAP Produced in response to various apoptotic stimuli and, by binding to IAPs and preventing their binding to a caspase, neutralize the inhibition of apoptosis provided by IAPs. antibiotic Substance such as penicillin or streptomycin that is toxic to microorganisms. Often a natural product of a particular microorganism or plant.


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Cell_Biology_Alberts. antibiotic Substance such as penicillin or streptomycin that is toxic to microorganisms. Often a natural product of a particular microorganism or plant. antibody Protein secreted by activated B cells in response to a pathogen or foreign molecule. Binds tightly to the pathogen or foreign molecule, inactivating it or marking it for destruction by phagocytosis or complement-induced lysis. (Figure 24–23) antibody response Adaptive immune response in which B cells are activated to secrete antibodies that circulate in the bloodstream or enter other body fluids, where they can bind specifically to the foreign antigen that stimulated their production. anticodon Sequence of three nucleotides in a transfer RNA (tRNA) molecule that is complementary to a three-nucleotide codon in a messenger RNA (mRNA) molecule. antigen A molecule that can induce an adaptive immune response or that can bind to an antibody or T cell receptor.