Immunology_Janeway

Immunology_Janeway. the dendritic cells to become activated (‘licensed’), which involves induction of the chemokine receptor CCr7 (second panel). TLr signaling also increases the processing of antigens taken up into phagosomes. dendritic cells expressing CCr7 are sensitive to CCL19 and CCL21, which direct them to the draining lymphoid tissue (third panel). CCL19 and CCL21 provide further maturation signals, which result in higher levels of co-stimulatory B7 molecules and MhC molecules. By the time they arrive in the draining lymph node, conventional dendritic cells have become powerful activators of naive T cells but are no longer phagocytic. They express B7.1, B7.2, and high levels of MhC class I and class II molecules, as well as high levels of the adhesion molecules ICaM-1, ICaM-2, LFa-1, and Cd58 (bottom panel).


Immunology_Janeway

Immunology_Janeway. CCL21 signaling through CCR7 not only induces the migration of dendritic cells into lymphoid tissue, but it also contributes to their enhanced antigen-presenting function (see Fig. 9.17, third panel). By the time activated dendritic cells arrive within lymphoid tissues, they are no longer able to engulf antigens by phagocytosis or macropinocytosis. They instead express very high levels of long-lived MHC class I and MHC class II molecules, which enable them to stably present peptides from pathogens already taken up and processed. Of equal importance, they express high levels of co-stimulatory molecules on their surface. There are two main co-stimulatory molecules: the structurally related transmembrane glycoproteins B7.1 (CD80) and B7.2 (CD86), which deliver co-stimulatory signals by interacting with receptors on naive T cells (see Section 7-21). Activated dendritic cells also express very high levels of adhesion molecules, including DC-SIGN, and they secrete the chemokine CCL19, which


Immunology_Janeway

Immunology_Janeway. with receptors on naive T cells (see Section 7-21). Activated dendritic cells also express very high levels of adhesion molecules, including DC-SIGN, and they secrete the chemokine CCL19, which specifically attracts naive T cells. Together, these properties enable the dendritic cell to stimulate strong responses in naive T cells (see Fig. 9.17, bottom panel).


Immunology_Janeway

Immunology_Janeway. Despite their enhanced presentation of pathogen-derived antigens, activated dendritic cells also present some self peptides, which could present a problem for the maintenance of self-tolerance. The T-cell receptor repertoire has, however, been purged of receptors that recognize self peptides presented in the thymus (see Chapter 8), so that T-cell responses against most ubiquitous self antigens are avoided. In addition, dendritic cells in the lymphoid tissues that have not been activated by infection will bear self-peptide:MHC complexes on their surface, derived from the breakdown of their own proteins and tissue proteins present in the extracellular fluid. Because these cells do not express the appropriate co-stimulatory molecules, however, they do not have the same capacity to activate naive T cells as do activated dendritic cells. Although the details are still unclear, the presentation of self peptides by lymph node-resident, or ‘unlicensed,’ dendritic cells may induce an


Immunology_Janeway

Immunology_Janeway. naive T cells as do activated dendritic cells. Although the details are still unclear, the presentation of self peptides by lymph node-resident, or ‘unlicensed,’ dendritic cells may induce an alternative program of activation in naive T cells that favors immune regulation rather than immune activation.


Immunology_Janeway

Immunology_Janeway. Intracellular degradation of pathogens reveals pathogen components other than peptides that trigger dendritic cell activation. For example, bacterial or viral DNA containing unmethylated CpG dinucleotide motifs induces the rapid activation of plasmacytoid dendritic cells as a consequence of recognition of the DNA by TLR-9, which is present in intracellular vesicles (see Fig. 3.10). Exposure to unmethylated DNA activates NFκB and mitogen-activated protein kinase (MAPK) signaling pathways (see Figs. 7.19–7.21), leading to the production of pro-inflammatory cytokines such as IL-6, IL-12, IL-18, and interferon (IFN)-α and IFN-β by dendritic cells. In turn, these cytokines act on the dendritic cells themselves to augment the expression of co-stimulatory molecules. Heat-shock proteins are another internal bacterial constituent that can activate the antigen-presenting function of dendritic cells. Similarly, some viruses are recognized by TLRs inside the dendritic cell via double-stranded RNA


Immunology_Janeway

Immunology_Janeway. internal bacterial constituent that can activate the antigen-presenting function of dendritic cells. Similarly, some viruses are recognized by TLRs inside the dendritic cell via double-stranded RNA produced during viral replication.


Immunology_Janeway

Immunology_Janeway. The induction of co-stimulatory activity in antigen-presenting cells by common microbial constituents is believed to allow the immune system to distinguish antigens borne by infectious agents from antigens associated with innocuous proteins, including self proteins. Indeed, many foreign proteins do not induce an immune response when injected on their own because they fail to induce co-stimulatory activity in antigen-presenting cells. When such protein antigens are mixed with bacteria, however, they become immunogenic, because the bacteria induce the essential co-stimulatory activity in cells that ingest the protein. Bacteria or bacterial components used in this way are known as adjuvants (see Appendix I, Section A-1). We will see in Chapter 15 how self proteins mixed with bacterial adjuvants can induce autoimmune disease, illustrating the crucial importance of the regulation of co-stimulatory activity in the discrimination of self from nonself.


Immunology_Janeway

Immunology_Janeway. interferons and may act as helper cells for antigen presentation by conventional dendritic cells.


Immunology_Janeway

Immunology_Janeway. Plasmacytoid dendritic cells are thought to act as sentinels in early defense against viral infection on the basis of their expression of TLRs and the intracellular nucleic acid-sensing RIG-I-like helicases, and their high production of antiviral type I interferons (see Sections 3-10 and 3-22). For several reasons, they are not thought to be involved in a major way in the antigen-specific activation of naive T cells. Plasmacytoid dendritic cells express fewer MHC class II and co-stimulatory molecules on their surface, and they process antigens less efficiently than conventional dendritic cells. In addition, unlike conventional dendritic cells, plasmacytoid dendritic cells do not cease the synthesis and recycling of MHC class II molecules after being activated. This means that they rapidly recycle their surface MHC II molecules and so cannot present pathogen-derived peptide:MHC complexes to T cells for extended periods, as conventional dendritic cells do.


Immunology_Janeway

Immunology_Janeway. Plasmacytoid dendritic cells may, however, act as helper cells for antigen presentation by conventional dendritic cells. This activity was revealed by studies in mice infected with the intracellular bacterium Listeria monocytogenes. Normally, IL-12 made by conventional dendritic cells induces CD4 T cells to produce abundant IFN-γ, which helps macrophages kill the bacteria. When plasmacytoid dendritic cells were experimentally eliminated, IL-12 production by conventional dendritic cells decreased, and the mice became susceptible to Listeria. It appears that plasmacytoid dendritic cells interact with conventional dendritic cells to sustain IL-12 production. Activation of plasmacytoid dendritic cells through TLR-9 induces the expression of CD40 ligand (CD40L or CD154), a TNF-family transmembrane cytokine, which binds to CD40, a TNF-family receptor that is expressed by activated conventional dendritic cells. This interaction enables conventional dendritic cells to sustain production of


Immunology_Janeway

Immunology_Janeway. cytokine, which binds to CD40, a TNF-family receptor that is expressed by activated conventional dendritic cells. This interaction enables conventional dendritic cells to sustain production of the pro-inflammatory cytokine IL-12, strengthening the IL-12-induced production of IFN-γ by T cells. Plasmacytoid dendritic cells can also produce IL-12 themselves, although in smaller amounts than conventional dendritic cells do.


Immunology_Janeway

Immunology_Janeway. 9-12 Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells.


Immunology_Janeway

Immunology_Janeway. The two other cell types that can act as antigen-presenting cells to T cells are macrophages and B cells, although there is an important distinction between the function of antigen presentation by these cells and that of dendritic cells. It is unlikely that macrophages and B cells present antigen to activate naive T cells. Rather, these cells present antigen to T cells that have already been primed by conventional dendritic cells as a means to recruit the effector, or ‘helper,’ functions of T cells that, in turn, provide signals to enhance their own effector functions. In this way, naive B cells that are activated by antigen bound to their surface immunoglobulin receptor present peptides derived from that antigen to elicit help from effector T cells in order to differentiate into immunoglobulin-secreting cells. And, as we learned in Chapter 3, while many microorganisms that enter the body are engulfed and destroyed by phagocytes, which provide an innate, antigen-nonspecific first line


Immunology_Janeway

Immunology_Janeway. cells. And, as we learned in Chapter 3, while many microorganisms that enter the body are engulfed and destroyed by phagocytes, which provide an innate, antigen-nonspecific first line of defense against infection, some pathogens have developed mechanisms to avoid elimination by innate immunity, such as resisting the killing properties of phagocytes. Macrophages that have ingested microorganisms but have failed to destroy them can use antigen presentation to recruit the adaptive immune response to enhance their microbicidal activities, as we will discuss further in Chapter 11.


Immunology_Janeway

Immunology_Janeway. Resting macrophages have few or no MHC class II molecules on their surface and do not express B7. The expression of both MHC class II molecules and B7 is induced by the ingestion of microorganisms and recognition of their microbe-associated molecular patterns (MAMPs). Macrophages, like dendritic cells, have a variety of pattern recognition receptors that recognize microbial surface components (see Chapter 3). Receptors such as Dectin-1, scavenger receptors, and complement receptors take up microorganisms into phagosomes, where they are degraded to produce peptides for presentation, while recognition of pathogen components via TLRs triggers intracellular signaling that contributes to the expression of MHC class II molecules and B7. However, unlike conventional dendritic cells, tissue-resident macrophages are generally nonmigratory; they do not traffic to T-cell zones of lymphoid tissues when activated by pathogens. It is thus likely that increased expression of MHC class II molecules


Immunology_Janeway

Immunology_Janeway. macrophages are generally nonmigratory; they do not traffic to T-cell zones of lymphoid tissues when activated by pathogens. It is thus likely that increased expression of MHC class II molecules and co-stimulatory molecules by activated macrophages is more important for locally amplifying T-cell responses already initiated by dendritic cells. This appears to be important for the maintenance and functioning of effector or memory T cells that enter a site of infection.


Immunology_Janeway

Immunology_Janeway. In addition to residing in tissues, macrophages are found in lymphoid organs (see Fig. 9.13). They are present in many areas of the lymph node, including the marginal sinus, where the afferent lymph enters the lymphoid tissue, and in the medullary cords, where the efferent lymph collects before flowing into the blood. However, they are largely sequestered from T-cell zones and are inefficient activators of naive T cells. Rather, their main function in lymphoid tissues appears to be the ingestion of microbes and particulate antigens to prevent them from entering the blood. They are also important scavengers of apoptotic lymphocytes.


Immunology_Janeway

Immunology_Janeway. Macrophages in other sites also continuously scavenge dead or dying cells, which are rich sources of self antigens, so it is particularly important that they should not activate naive T cells. The Kupffer cells of the liver sinusoids and the macrophages of the splenic red pulp, in particular, remove large numbers of dying cells from the blood daily. Kupffer cells express little MHC class II and no TLR-4, the receptor that signals the presence of bacterial LPS. Thus, although they generate large amounts of self peptides in their endosomes, these macrophages are not likely to elicit an immune response. 9-13 B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin.


Immunology_Janeway

Immunology_Janeway. B cells are uniquely adapted to bind specific soluble molecules through their membrane-bound antigenic receptor, or B-cell receptor (BCR), the antigen-binding component of which is membrane-associated IgM, which is highly efficient at internalizing the bound molecules by receptor-mediated endocytosis. If the antigen contains a protein component, the B cell will process the internalized protein to peptide fragments and then display the fragments as peptide:MHC class II complexes. Through this mechanism B cells are able to take up and present even low concentrations of specific antigen to T cells. B cells also constitutively express high levels of MHC class II molecules, and so high levels of specific peptide:MHC class II complexes appear on the B-cell surface (Fig. 9.18). As we will see in Chapter 10, this pathway of antigen presentation allows the B cell to specifically interact with a CD4 T cell that has been previously activated by the same antigen as a mechanism to receive signals


Immunology_Janeway

Immunology_Janeway. Chapter 10, this pathway of antigen presentation allows the B cell to specifically interact with a CD4 T cell that has been previously activated by the same antigen as a mechanism to receive signals from the T cell to drive the B cell's differentiation into an antibody-producing cell.


Immunology_Janeway

Immunology_Janeway. B cells do not constitutively express co-stimulatory molecules, but, as with dendritic cells and macrophages, they can be induced by various microbial constituents to express B7 molecules. In fact, B7.1 was first identified as a protein on B cells activated by LPS, and B7.2 is predominantly expressed by B cells in vivo. Soluble protein antigens are not abundant during infections; most natural antigens, such as bacteria and viruses, are particulate, and many soluble bacterial toxins act by binding to cell surfaces and so are present only at low concentrations in solution. Some natural immunogens enter the body as soluble molecules, however; examples are bacterial toxins, anticoagulants injected by blood-sucking insects, snake venoms, and many allergens. Nevertheless, it is unlikely that B cells are important in priming naive T cells to soluble antigens in natural immune responses. Tissue dendritic cells can take up soluble antigens by macropinocytosis, and although they cannot


Immunology_Janeway

Immunology_Janeway. that B cells are important in priming naive T cells to soluble antigens in natural immune responses. Tissue dendritic cells can take up soluble antigens by macropinocytosis, and although they cannot concentrate these antigens as antigen-specific B cells do, dendritic cells are more likely to encounter a naive T cell with the appropriate antigen specificity than are the extremely limited number of antigen-specific B cells. The chances of a B cell encountering a T cell that can recognize the peptide antigens it displays are greatly increased once a naive T cell has been detained in lymphoid tissue by finding its antigen on the surface of a dendritic cell and has undergone clonal expansion.


Immunology_Janeway

Immunology_Janeway. High density of speciÿc antigen fragments are presented at the B-cell surface Speciÿc antigen is efÿciently internalized by receptor-mediated endocytosis Fig. 9.18 B cells can use their surface immunoglobulin to present specific antigen very efficiently to T cells. The three types of antigen-presenting cells are compared in Fig. 9.19. In each of these cell types the expression of co-stimulatory activity is controlled so as to provoke responses against pathogens while avoiding immunization against self.


Immunology_Janeway

Immunology_Janeway. surface immunoglobulin allows B cells to bind and internalize specific antigen very efficiently, especially if the antigen is present as a soluble protein, as most toxins are. The internalized antigen is processed in intracellular vesicles, where it binds to MhC class II molecules. The vesicles are transported to the cell surface, where the foreign-peptide:MhC class II complexes can be recognized by T cells. When the protein antigen is not specific for the B-cell receptor, its internalization is inefficient and only a few fragments of such proteins are subsequently presented at the B-cell surface (not shown).


Immunology_Janeway

Immunology_Janeway. Fig. 9.19 The properties of the various antigen-presenting cells. dendritic cells, macrophages, and B cells are the main cell types involved in the presentation of foreign antigens to T cells. These cells vary in their means of antigen uptake, MhC class II expression, co-stimulator expression, the type of antigen they present effectively, their locations in the body, and their surface adhesion molecules (not shown). antigen presentation by dendritic cells is primarily involved in activating naive T cells for expansion and differentiation. Macrophages and B cells present antigen primarily to receive specific help from effector T cells in the form of cytokines or surface molecules. Summary.


Immunology_Janeway

Immunology_Janeway. Summary. An adaptive immune response is generated when naive T cells contact activated antigen-presenting cells in the secondary lymphoid organs. These tissues have a specialized architecture that facilitates efficient interaction between circulating lymphocytes and their target antigens. The formation and organization of the peripheral lymphoid organs are controlled by proteins of the TNF family and their receptors (TNFRs). Lymphoid tissue inducer (LTi) cells expressing lymphotoxin-β (LT-β) interact with stromal cells expressing the LT-β receptor in the developing embryo to induce chemokine production, which in turn initiates formation of the lymph nodes and Peyer’s patches. Similar interactions between lymphotoxin-expressing B cells and TNFR-Iexpressing follicular dendritic cells (FDCs) establish the normal architecture of the spleen and lymph nodes. B and T cells are partitioned into distinct areas within lymphoid tissue by specific chemokines.


Immunology_Janeway

Immunology_Janeway. To ensure that rare antigen-specific T cells survey the body effectively for pathogen-bearing antigen-presenting cells, T cells continuously recirculate through the lymphoid organs and thus can sample antigens brought in by antigen-presenting cells from many different tissue sites. The migration of naive T cells into lymphoid organs is guided by the chemokine receptor CCR7, which binds CCL21 that is produced by stromal cells in the T-cell zones of secondary lymphoid tissues and is displayed on the specialized endothelium of HEVs. L-selectin expressed by naive T cells initiates their rolling along the specialized surfaces of high endothelial venules, where contact with CCL21 induces a switch in the integrin LFA-1 expressed by T cells to a configuration with affinity for the ICAM-1 expressed on the venule endothelium. This initiates strong adhesion, diapedesis, and migration of the T cells into the T-cell zone. There, naive T cells meet antigen-bearing dendritic cells, of which there


Immunology_Janeway

Immunology_Janeway. on the venule endothelium. This initiates strong adhesion, diapedesis, and migration of the T cells into the T-cell zone. There, naive T cells meet antigen-bearing dendritic cells, of which there are two main populations: conventional dendritic cells, and plasmacytoid dendritic cells. Conventional dendritic cells continuously survey secondary tissues for invading pathogens and are the dendritic cells responsible for activating naive T cells. Contact with pathogens delivers signals to dendritic cells via TLRs and other receptors that accelerate antigen processing and the production of for-eign-peptide:self MHC complexes. TLR signaling also induces expression of CCR7 by dendritic cells, which directs their migration to T-cell zones of secondary lymphoid organs, where they encounter and activate naive T cells.


Immunology_Janeway

Immunology_Janeway. Macrophages and B cells can also process particulate or soluble antigens from pathogens to be presented as peptide:MHC complexes to T cells. However, whereas antigen presentation to naive T cells is uniquely mediated by dendritic cells, antigen presentation by macrophages and B cells enables the latter two cell types to recruit the effector activities of previously activated antigen-specific T cells. For example, as discussed in Chapter 11, by presenting antigens of ingested pathogens, macrophages recruit help from IFN-γ-producing CD4 T cells to augment their intracellular killing of these pathogens. Presentation of antigens by B cells recruits help from T cells to stimulate antibody production and class switching, a topic discussed further in Chapter 10. In all three types of antigen-presenting cells, the expression of co-stimulatory molecules is activated in response to signals from receptors that also function in innate immunity to signal the presence of infectious agents.


Immunology_Janeway

Immunology_Janeway. Priming of naive T cells by pathogen-activated dendritic cells. T-cell responses are initiated when a mature naive CD4 or CD8 T cell encounters an activated antigen-presenting cell displaying the appropriate peptide:MHC ligand. We will now describe the generation of effector T cells from naive T cells. The activation and differentiation of naive T cells, often called priming, is distinct from the later responses of effector T cells to antigen on their target cells, and from the responses of primed memory T cells to subsequent encounters with the same antigen. Priming of naive CD8 T cells generates cytotoxic T cells capable of directly killing pathogen-infected cells. CD4 cells develop into a diverse array of effector cell types depending on the nature of the signals they receive during priming. CD4 effector activity can also include cytotoxicity, but more frequently it involves the secretion of a set of cytokines, which direct target cells toward a more pathogen-specific response.


Immunology_Janeway

Immunology_Janeway. 9-14 Cell-adhesion molecules mediate the initial interaction of naive T cells with antigen-presenting cells. As they migrate through the cortical region of the lymph node, naive T cells bind transiently to each antigen-presenting cell that they encounter. Activated dendritic cells bind naive T cells very efficiently through interactions between LFA-1 and CD2 on the T cell and ICAM-1, ICAM-2, and CD58 on the dendritic cell (Fig. 9.20). Perhaps because of this synergy, the precise role of each adhesion molecule has been difficult to distinguish. People lacking LFA-1 can have normal T-cell responses, and this also seems to be true for genetically engineered mice lacking CD2, suggesting substantial redundancy in the function of these molecules.


Immunology_Janeway

Immunology_Janeway. The transient binding of naive T cells to antigen-presenting cells is crucial in providing time for a T cell to sample large numbers of MHC molecules for the presence of its cognate antigenic peptide. In those rare cases in which a naive T cell recognizes its peptide:MHC ligand, signaling through the T-cell receptor induces a conformational change in LFA-1 that greatly increases its affinity for ICAM-1 and ICAM-2. This conformational change is the same as that induced by signaling through CCR7 during the migration of naive T cells into a secondary lymphoid organ (see Section 9-6). The change in LFA-1 stabilizes the association between the antigen-specific T cell and the antigen-presenting cell (Fig. 9.21). The association can persist for several days, during which time the naive T cell proliferates and its progeny, which can also adhere to the antigen-presenting cell, differentiate into effector T cells.


Immunology_Janeway

Immunology_Janeway. Most encounters of T cells with antigen-presenting cells do not, however, result in the recognition of an antigen. In this case, the T cell must be able to separate efficiently from the antigen-presenting cell so that it can continue to migrate through the lymphoid tissue, eventually exiting to reenter the blood and continue circulating. Dissociation, like stable binding, may also involve signaling between the T cell and the antigen-presenting cells, but little is known of its mechanism. Conformational change in LFA-1 increases afÿnity and prolongs cell–cell contact Subsequent binding of T-cell receptors signals LFA-1 Fig. 9.21 Transient adhesive interactions between T cells and antigen-presenting cells are stabilized by specific antigen recognition.


Immunology_Janeway

Immunology_Janeway. Fig. 9.21 Transient adhesive interactions between T cells and antigen-presenting cells are stabilized by specific antigen recognition. Fig. 9.20 Cell-surface molecules of the immunoglobulin superfamily are important in the interactions of lymphocytes with antigen-presenting cells. In the initial encounter of T cells with antigen-presenting cells, Cd2 binding to Cd58 on the antigen-presenting cell synergizes with LFa-1 binding to ICaM-1 and ICaM-2. LFa-1 is the αL:β2 integrin heterodimer Cd11a:Cd18. ICaM-1 and ICaM-2 are also known as Cd54 and Cd102, respectively. MOVIE XX.X When a T cell binds to its specific ligand on an antigen-presenting cell, intracellular signaling through the T-cell receptor (TCr) induces a conformational change in LFa-1 that causes it to bind with higher affinity to ICaMs on the antigen-presenting cell. The T cell shown here is a Cd4 T cell.


Immunology_Janeway

Immunology_Janeway. on resting T cells, the β and γ chains are expressed constitutively. They bind IL-2 with moderate affinity. activation of T cells induces the synthesis of the α chain and the formation of the high-affinity heterotrimeric receptor. The β and γ chains show similarities in amino acid sequence to cell-surface receptors for growth hormone and prolactin, each of which also regulates cell growth and differentiation.


Immunology_Janeway

Immunology_Janeway. Fig. 9.22 Three kinds of signals are involved in activation of naive T cells by antigen-presenting cells. Binding of the foreign-peptide:self MhC complex by the T-cell receptor and, in this example, a Cd4 co-receptor transmits a signal (arrow 1) to the T cell that antigen has been encountered. effective activation of naive T cells requires a second signal (arrow 2), the co-stimulatory signal, to be delivered by the same antigen-presenting cell (apC). In this example, Cd28 on the T cell encountering B7 molecules on the antigen-presenting cell delivers signal 2, whose net effect is the increased survival and proliferation of the T cell that has received signal 1. ICos and various members of the TnF receptor family may also provide co-stimulatory signals. For Cd4 T cells in particular, different pathways of differentiation produce subsets of effector T cells that carry out different effector responses, depending on the nature of a third signal (arrow 3) delivered by the


Immunology_Janeway

Immunology_Janeway. particular, different pathways of differentiation produce subsets of effector T cells that carry out different effector responses, depending on the nature of a third signal (arrow 3) delivered by the antigen-presenting cell. Cytokines are commonly, but not exclusively, involved in directing this differentiation.


Immunology_Janeway

Immunology_Janeway. 9-15 Antigen-presenting cells deliver multiple signals for the clonal expansion and differentiation of naive T cells.


Immunology_Janeway

Immunology_Janeway. When discussing the activation of naive T cells, it is useful to consider at least three different types of signals (Fig. 9.22). The first signal is generated from the interaction of a specific peptide:MHC complex with the T-cell receptor. Engagement of the T-cell receptor with its specific peptide antigen is essential for activating a naive T cell. However, even if the co-receptor—CD4 or CD8—is also ligated, this does not, on its own, stimulate the T cell to fully proliferate and differentiate into effector T cells. Expansion and differentiation of naive T cells involve at least two other kinds of signals: co-stimulatory signals that promote the survival and expansion of the T cells, and cytokines that direct T-cell differentiation into one of the different subsets of effector T cells. Additional signals, such as Notch ligands, can contribute to the effector differentiation of naive T cells, although these signals appear to be of lesser importance than those of lineage-specifying


Immunology_Janeway

Immunology_Janeway. Additional signals, such as Notch ligands, can contribute to the effector differentiation of naive T cells, although these signals appear to be of lesser importance than those of lineage-specifying cytokines.


Immunology_Janeway

Immunology_Janeway. The best-characterized co-stimulatory molecules are the B7 molecules. These homodimeric members of the immunoglobulin superfamily are found exclusively on the surfaces of cells, such as dendritic cells, that stimulate naive T-cell proliferation (see Section 9-8). The receptor for B7 molecules on the T cell is CD28, a member of the immunoglobulin superfamily (see Section 7-21). Ligation of CD28 by B7 molecules is necessary for the optimal clonal expansion of naive T cells; targeted deficiency of B7 molecules or experimental blockade of the binding of B7 molecules to CD28 has been shown to inhibit T-cell responses. 9-16 CD28-dependent co-stimulation of activated T cells induces expression of interleukin-2 and the high-affinity IL-2 receptor.


Immunology_Janeway

Immunology_Janeway. Naive T cells are found as small resting cells with condensed chromatin and scanty cytoplasm, and they synthesize little RNA or protein. On activation, they reenter the cell cycle and divide rapidly to produce large numbers of progeny as they undergo antigen-driven differentiation. Unlike effector T cells, which can produce a diversity of cytokines depending on the mature effector phenotype, naive T cells primarily produce interleukin-2 (IL-2) when activated. Based on in vitro studies, IL-2 was long thought to be required for the proliferation of naive T cells. However, in vivo studies indicate that while IL-2 can augment T-cell proliferation and survival, in many cases it is dispensable and other functions of IL-2 might be more important. In particular, IL-2 is essential for the maintenance of regulatory T cells, which do not produce their own IL-2 when activated. IL-2 also appears to affect the balance of effector and memory T cells that develop in a primary response to antigen, as


Immunology_Janeway

Immunology_Janeway. of regulatory T cells, which do not produce their own IL-2 when activated. IL-2 also appears to affect the balance of effector and memory T cells that develop in a primary response to antigen, as will be discussed in Chapter 11.


Immunology_Janeway

Immunology_Janeway. The initial encounter with specific antigen in the presence of a co-stimulatory signal triggers entry of the T cell into the G1 phase of the cell cycle; at the same time, it also induces the synthesis of IL-2 along with the α chain of the IL-2 receptor (also known as CD25). The IL-2 receptor is composed of three chains: α, β, and γ (Fig. 9.23). Prior to activation, naive T cells express a form of the receptor composed only of the βand γ chains, which has only moderate affinity for IL-2 binding. Within hours of activation, naive T cells upregulate the expression of CD25. Association of CD25 with the βand γ heterodimer creates a receptor with a much higher affinity for IL-2, allowing the T cell to respond to very low concentrations of IL-2. In contrast to naive T cells, regulatory T, or T , cells constitutively express


Immunology_Janeway

Immunology_Janeway. In contrast to naive T cells, regulatory T, or T , cells constitutively express CD25, and thus the high-affinity, trimeric form of the IL-2 receptor (see Fig. 9.23). As is discussed later (see Section 9-23), it is thought that by expressing the high-affinity form of the IL-2 receptor, T cells can outcompete T cells that express only the low-affinity form of the receptor for binding of the limited quantities of IL-2 that are available early in the response to antigen. In this way, T cells act as a ‘sink’ for IL-2 to limit its availability to other cells.


Immunology_Janeway

Immunology_Janeway. However, once activated naive T cells have upregulated CD25, they form the high-affinity receptor and compete with T cells for binding of IL-2. The bind- ing of IL-2 by these activated naive T cells triggers signaling that supports their activation and differentiation, and can enhance their proliferation (Fig. 9.24). T cells activated in this way can divide up to four times a day for several days, allowing one precursor cell to give rise to thousands of clonal progeny that all bear the same antigenic receptor.


Immunology_Janeway

Immunology_Janeway. Antigen recognition by the T-cell receptor induces the synthesis or activation of the transcription factors NFAT, AP-1, and NFκB, which bind to the promoter region of the IL-2 gene in naive T cells to activate its transcription (see Sections 7-14 and 7-16). Co-stimulation through CD28 contributes to the production of IL-2 in at least three ways. First, CD28 signaling activates PI 3-kinase, which increases production of the AP-1 and NFκB transcription factors, thereby increasing the transcription of IL-2 mRNA. However, the mRNAs of many cytokines, including IL-2, are very short-lived because of an ‘instability’ sequence (AUUUAUUUA) in the 3' untranslated region. CD28 signaling prolongs the lifetime of an IL-2 mRNA molecule by inducing the expression of proteins that block the activity of the instability sequence, resulting in increased translation and more IL-2 protein. Finally, PI 3-kinase helps activate the protein kinase Akt (see Section 7-17), which generally promotes cell growth


Immunology_Janeway

Immunology_Janeway. the instability sequence, resulting in increased translation and more IL-2 protein. Finally, PI 3-kinase helps activate the protein kinase Akt (see Section 7-17), which generally promotes cell growth and survival, increasing the total production of IL-2 by activated T cells.


Immunology_Janeway

Immunology_Janeway. 9-17 Additional co-stimulatory pathways are involved in T-cell activation. Once a naive T cell is activated, it expresses a number of proteins in addition to CD28 that contribute to sustaining or modifying the co-stimulatory signal. These other co-stimulatory receptors generally belong to either the CD28 or the TNF receptor family.


Immunology_Janeway

Immunology_Janeway. CD28-related proteins are expressed on activated T cells and modify the co-stimulatory signal as the T-cell response develops. One such protein is the inducible co-stimulator (ICOS), which binds a ligand known as ICOSL (ICOS ligand, or B7-H2), a structural relative of B7.1 and B7.2. ICOSL is produced on activated dendritic cells, monocytes, and B cells. Although ICOS resembles CD28 in driving T-cell proliferation, it does not induce IL-2 but seems to regulate the expression of other cytokines, such as IL-4 and IFN-γ, made by CD4 T-cell subsets. ICOS is particularly important for enabling CD4 T cells to function as helper cells for B-cell responses such as isotype switching. ICOS is expressed on T cells in germinal centers within lymphoid follicles, and mice lacking ICOS fail to develop germinal centers and have severely diminished antibody responses.


Immunology_Janeway

Immunology_Janeway. Another receptor for B7 molecules is CTLA-4 (CD152), which is related in sequence to CD28. CTLA-4 binds B7 molecules about 20 times more avidly Fig. 9.24 Activated T cells secrete and respond to IL-2. activation of naive T cells induces the expression and secretion of IL-2 and the expression of high-affinity IL-2 receptors. IL-2 binds to the high-affinity IL-2 receptors to enhance T-cell growth and differentiation. CTLA-4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells activated T cell antigen-presenting cell MHC class II CD4 + TCRCTLA-4 B7.1


Immunology_Janeway

Immunology_Janeway. CTLA-4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells activated T cell antigen-presenting cell MHC class II CD4 + TCRCTLA-4 B7.1 Fig. 9.25 CTLA-4 is an inhibitory receptor for B7 molecules. naive T cells express Cd28, which delivers a co-stimulatory signal on binding B7 molecules (see Fig. 9.22), thereby driving the survival and expansion of the T cells. activated T cells express increased levels of CTLa-4 (Cd152), which has a higher affinity than Cd28 for B7 molecules and thus binds most or all of the B7 molecules. CTLa-4 thereby serves to regulate the proliferative phase of the T-cell response.


Immunology_Janeway

Immunology_Janeway. than CD28, but its effect is to inhibit, rather than activate, the T cell (Fig. 9.25). CTLA-4 does not contain an ITIM motif, and it is suggested to inhibit T-cell activation by competing with CD28 for interaction with B7 molecules expressed by antigen-presenting cells. Activation of naive T cells induces the surface expression of CTLA-4, making activated T cells less sensitive than naive T cells to stimulation by the antigen-presenting cell, thereby restricting IL-2 production. Thus, binding of CTLA-4 to B7 molecules is essential for limiting the proliferative response of activated T cells to antigen and B7. This was confirmed by producing mice with a disrupted CTLA-4 gene; such mice develop a fatal disorder characterized by a massive overgrowth of lymphocytes. Antibodies that block CTLA-4 from binding to B7 molecules markedly increase T cell-dependent immune responses.


Immunology_Janeway

Immunology_Janeway. Several TNF-family molecules also deliver co-stimulatory signals. These all seem to function by activating NFκB through a TRAF-dependent pathway (see Section 7-23). The binding of CD70 on dendritic cells to its constitutively expressed CD27 receptor on naive T cells delivers a potent co-stimulatory signal to T cells early in the activation process. The receptor CD40 on dendritic cells binds to CD40 ligand expressed on T cells, initiating two-way signaling that transmits activating signals to the T cell and also induces the dendritic cell to express increased B7, thus stimulating further T-cell proliferation. The role of the CD40–CD40 ligand pair in sustaining a T-cell response is demonstrated in mice lacking CD40 ligand; when these mice are immunized, the clonal expansion of responding T cells is curtailed at an early stage. The T-cell molecule 4-1BB (CD137) and its ligand 4-1BBL, which is expressed on activated dendritic cells, macrophages, and B cells, make up another pair of


Immunology_Janeway

Immunology_Janeway. T cells is curtailed at an early stage. The T-cell molecule 4-1BB (CD137) and its ligand 4-1BBL, which is expressed on activated dendritic cells, macrophages, and B cells, make up another pair of TNF-family co-stimulators. The effects of this interaction are also bidirectional, with both the T cell and the antigen-presenting cell receiving activating signals; this type of interaction is sometimes referred to as the T-cell:antigen-presenting cell dialog. Another co-stimulatory receptor and its ligand, OX40 and OX40L, are expressed on activated T cells and dendritic cells, respectively. Mice deficient in OX40 show reduced CD4 T-cell proliferation in response to viral infection, indicating that OX40 has a role in sustaining ongoing T-cell responses by enhancing T-cell survival and proliferation.


Immunology_Janeway

Immunology_Janeway. 9-18 Proliferating T cells differentiate into effector T cells that do not require co-stimulation to act.


Immunology_Janeway

Immunology_Janeway. During the 4–5 days of rapid cell division that follow naive T-cell activation, T cells differentiate into effector T cells that acquire the ability to synthesize molecules required for their specialized helper or cytotoxic functions when they re-encounter their specific antigen. Effector T cells undergo additional changes that distinguish them from naive T cells. One of the most important is in their activation requirements: once a T cell has differentiated into an effector cell, encounter with its specific antigen results in immune attack without the need for co-stimulation (Fig. 9.26). This distinction is particularly easy to understand for CD8 cytotoxic T cells, which must be able to act on any cell infected with a virus, whether or not the infected cell can express co-stimulatory molecules. However, this feature is also important for the effector function of CD4 cells, as effector CD4 T cells must be able to activate B cells and macrophages that have taken up antigen even if


Immunology_Janeway

Immunology_Janeway. molecules. However, this feature is also important for the effector function of CD4 cells, as effector CD4 T cells must be able to activate B cells and macrophages that have taken up antigen even if these cells are not initially expressing co-stimulatory molecules.


Immunology_Janeway

Immunology_Janeway. Changes are also seen in the cell-adhesion molecules and receptors expressed by effector T cells. They lose cell-surface L-selectin and therefore cease to recirculate through lymph nodes. Instead, they express glycans that serve as ligands for Pand E-selectins (for example, P-selectin glycoprotein-1, or PSGL-1), which are upregulated on inflamed vascular endothelial cells and


Immunology_Janeway

Immunology_Janeway. Fig. 9.26 Effector T cells can respond to their target cells effector cell status (central panel). once the cells have differentiated without co-stimulation. a naive T cell that recognizes antigen on into effector T cells, any encounter with specific antigen triggers the surface of an antigen-presenting cell and receives the required their effector actions without the need for co-stimulation. Thus, as two signals (arrows 1 and 2, left panel) becomes activated, and it illustrated here, a cytotoxic T cell can kill any virus-infected target both secretes and responds to IL-2. IL-2 signaling enhances clonal cells, including those that do not express co-stimulatory molecules. expansion and contributes to the differentiation of the T cells to allow effector T cells to roll on the blood vessels at sites of inflammation. They also express higher levels of LFA-1 and CD2 than do naive T cells, as well as the integrin VLA-4, which allows them to bind to vascular endothelium bearing the adhesion


Immunology_Janeway

Immunology_Janeway. at sites of inflammation. They also express higher levels of LFA-1 and CD2 than do naive T cells, as well as the integrin VLA-4, which allows them to bind to vascular endothelium bearing the adhesion molecule VCAM-1, which is also expressed on the inflamed endothelium. This allows effector T cells to exit the bloodstream and enter sites of infection, where they orchestrate the local immune response. These changes in the T-cell surface are summarized in Fig. 9.27, and will be discussed further in Chapter 11.


Immunology_Janeway

Immunology_Janeway. Fig. 9.27 Activation of T cells changes the expression of several cell-surface molecules. The example here is a Cd4 T cell. resting naive T cells express L-selectin, through which they home to lymph nodes, but express relatively low levels of other adhesion molecules such as Cd2 and LFa-1. upon activation, expression of L-selectin ceases and, instead, expression of ligands for pand e-selectins are induced (e.g., psGL-1), which allow the activated T cells to roll on pand e-selectins expressed on endothelium at sites of inflammation. Increased amounts of the integrin LFa-1 are also produced, which is activated to bind its ligands, ICaM-1 and ICaM-2. a newly expressed integrin called vLa-4, which allows T cells to arrest on inflamed vascular endothelium, ensures that activated T cells enter peripheral tissues at sites where they are likely to encounter infection. activated T cells also have on their surface a higher density of the adhesion molecule Cd2, increasing the avidity of their


Immunology_Janeway

Immunology_Janeway. peripheral tissues at sites where they are likely to encounter infection. activated T cells also have on their surface a higher density of the adhesion molecule Cd2, increasing the avidity of their interaction with potential target cells, as well as a higher density of the adhesion molecule Cd44. By alternative splicing of the rna transcript of the Cd45 gene, a change occurs in the isoform of Cd45 that is expressed, with activated T cells expressing the Cd45ro isoform, which associates with the T-cell receptor and Cd4. This change makes the T cell more sensitive to stimulation by low concentrations of peptide:MhC complexes. Finally, the sphingosine 1-phosphate receptor 1(s1pr1) is expressed by resting naive T cells, allowing the egress from lymphoid tissues of cells that do not become activated (see Fig. 9.11). downregulation of s1pr1 for several days after activation prevents T-cell egress during the period of proliferation and differentiation. after several days, it is expressed


Immunology_Janeway

Immunology_Janeway. activated (see Fig. 9.11). downregulation of s1pr1 for several days after activation prevents T-cell egress during the period of proliferation and differentiation. after several days, it is expressed again, allowing effector cells to exit from the lymphoid tissues.


Immunology_Janeway

Immunology_Janeway. 9-19 CD8 T cells can be activated in different ways to become cytotoxic effector cells. Naive T cells fall into two large classes, of which one carries the co-receptor CD8 on its surface and the other bears the co-receptor CD4. CD8 T cells all differentiate into CD8 cytotoxic T cells (sometimes called cytotoxic lymphocytes, or CTLs), which kill their target cells (Fig. 9.28). They are important in the defense against intracellular pathogens, especially viruses. Virus-infected cells display fragments of viral proteins as peptide:MHC class I complexes on their surface, and these are recognized by cytotoxic T lymphocytes.


Immunology_Janeway

Immunology_Janeway. Perhaps because the effector actions of these cells are so destructive, naive CD8 T cells require more co-stimulatory activity to drive them to become activated effector cells than do naive CD4 T cells. This requirement can be met in two ways. The simplest is priming by activated dendritic cells, which have high intrinsic co-stimulatory activity. In some viral infections, dendritic cells become sufficiently activated to directly induce CD8 T cells to produce the IL-2 required for their differentiation into cytotoxic effector cells, without help from CD4 T cells. This property of dendritic cells has been exploited to generate cytotoxic T-cell responses against tumors, as we will see in Chapter 16.


Immunology_Janeway

Immunology_Janeway. In the majority of viral infections, however, CD8 T-cell activation requires additional help, which is provided by CD4 effector T cells. CD4 T cells that recognize related antigens presented by the antigen-presenting cell can amplify the activation of naive CD8 T cells by further activating the antigen-presenting cell (Fig. 9.29). B7 expressed by the dendritic cell first activates the CD4 T cells to express IL-2 and CD40 ligand (see Sections 9-16 and 9-17). CD40 ligand binds CD40 on the dendritic cell, delivering an additional signal that increases the expression of B7 and 4-1BBL by the dendritic cell, which in turn provides additional co-stimulation to the naive CD8 T cell. The IL-2 produced by activated CD4 T cells also acts to promote effector CD8 T-cell differentiation. 9-20 CD4 T cells differentiate into several subsets of functionally different effector cells.


Immunology_Janeway

Immunology_Janeway. 9-20 CD4 T cells differentiate into several subsets of functionally different effector cells. In contrast with CD8 T cells, CD4 T cells differentiate into several subsets of effector T cells that orchestrate different immune functions. The main functional subsets are TH1 (T helper 1), TH2, TH17, T follicular helper (TFH), and regulatory T (Treg) cells. The TH1, TH2, and TH17 subsets are elicited by different classes of pathogens and are defined on the basis of the different combinations of cytokines that they secrete (Fig. 9.30). These subsets cooperate with different innate cells of the myelomonocytic series and with innate lymphoid cells (ILCs) to form integrated ‘immune modules’ specialized for the clearance of the different classes of pathogens (see Fig. 3.37). One or the other of these subsets will typically become predominant as an immune response progresses, especially in persistent infections, autoimmunity, or allergies. As


Immunology_Janeway

Immunology_Janeway. Fig. 9.29 Most CD8 T-cell responses require CD4 T cells. Cd8 T cells recognizing antigen on weakly co-stimulatory cells may become activated only in the presence of Cd4 T cells interacting with the same antigen-presenting cell (apC). This happens mainly by an effector Cd4 T cell recognizing antigen on the antigen-presenting cell and being triggered to induce increased levels of co-stimulatory activity on the antigen-presenting cell. The Cd4 T cells also produce abundant IL-2 and thus help drive Cd8 T-cell proliferation. This may in turn activate the Cd8 T cell to make its own IL-2.


Immunology_Janeway

Immunology_Janeway. Fig. 9.30 Subsets of CD4 effector T cells are specialized to provide help to different target cells for the eradication of different classes of pathogens. unlike Cd8 T cells, which act directly on infected target cells to eliminate pathogens, Cd4 T cells typically enhance the effector functions of other cells that eradicate pathogens—whether cells of the innate immune system, or, in the case of TFh cells, antigen-specific B cells. Th1 cells (first panels) produce cytokines, such as IFn-γ, which activate macrophages, enabling them to destroy intracellular microorganisms more efficiently. Th2 cells (second panels) produce cytokines that recruit and activate eosinophils (IL-5) and mast cells and basophils (IL-4), and promote enhanced barrier immunity at mucosal surfaces (IL-13) to eradicate helminths. Th17 cells (third panels) secrete IL-17-family cytokines that induce local epithelial and stromal cells to produce chemokines that recruit neutrophils to sites of infection. Th17 cells also


Immunology_Janeway

Immunology_Janeway. Th17 cells (third panels) secrete IL-17-family cytokines that induce local epithelial and stromal cells to produce chemokines that recruit neutrophils to sites of infection. Th17 cells also produce IL-22, which along with IL-17 can activate epithelial cells at the barrier site to produce antimicrobial peptides that kill bacteria. TFh cells (fourth panels) form cognate interactions with naive B cells through linked recognition of antigen and traffic to B-cell follicles, where they promote the germinal center response. TFh cells produce cytokines characteristic of other subsets and participate in type 1, 2, and 3 responses that are recruited against different types of pathogens. TFh cells producing IFn-γ activate B cells to produce strongly opsonizing antibodies belonging to certain IgG subclasses (IgG1 and IgG3 in humans, and their homologs, IgG2a and IgG2b, in the mouse) in type 1 responses. Those TFh cells producing IL-4 drive B cells to differentiate and produce immunoglobulin Ige,


Immunology_Janeway

Immunology_Janeway. (IgG1 and IgG3 in humans, and their homologs, IgG2a and IgG2b, in the mouse) in type 1 responses. Those TFh cells producing IL-4 drive B cells to differentiate and produce immunoglobulin Ige, which arms mast cells and basophils for granule release in type 2 responses. TFh cells that produce IL-17 appear to be important for generating opsonizing antibodies directed against extracellular pathogens in the context of type 3/Th17 immunity. regulatory T cells (right panels) generally suppress T-cell and innate immune cell activity and help prevent the development of autoimmunity during immune responses.


Immunology_Janeway

Immunology_Janeway. we shall discuss further in Chapter 11, the functional features of these T-cell subsets parallel in many ways those of innate lymphoid cells (ILCs), which, although lacking antigenic receptors, produce many of the same patterns of effector cytokines or cytotoxins. The first CD4 T-cell subsets to be distinguished were the TH1 and TH2 subsets, hence their names. TH1 cells are characterized by the production of IFN-γ, whereas TH2 cells are characterized by the production of IL-4, IL-5, and IL-13. TH17 cells are so named because they produce the cytokines IL-17A and IL-17F; they also produce IL-22. TFH cells develop in concert with TH1, TH2, or TH17 cells to help B cells generate class-switched immunoglobulins of different isotypes, which are targeted to different innate immune effector cells by the array of Fc receptors they display. Treg cells have immunoregulatory function and promote tolerance to, rather than clearance of, the antigens they recognize.


Immunology_Janeway

Immunology_Janeway. TH1 cells help to eradicate infections by microbes that can survive or replicate within macrophages. Examples include certain viruses, protozoans, and intracellular bacteria, such as the mycobacteria that cause tuberculosis and leprosy. These bacteria are phagocytosed by macrophages in the usual way but can evade the intracellular killing mechanisms described in Chapter 3. If a TH1 cell recognizes bacterial antigens displayed on the surface of an infected macrophage, it will activate the macrophage further through the release of IFN-γ, which enhances the macrophage’s microbicidal activity to kill ingested bacteria. Type 1 responses also promote B-cell class switching that favors production of opsonizing IgG antibodies, such as IgG2a in mouse. We shall describe the macrophage-activating functions of TH1 cells in more detail in Chapter 11.


Immunology_Janeway

Immunology_Janeway. TH2 cells help to control infections by extracellular parasites, particularly helminths, by promoting responses mediated by eosinophils, mast cells, and IgE. In particular, cytokines produced as part of a type 2 response are required for class switching of B cells to produce IgE, the primary role of which is to fight parasitic infections. IgE is also the antibody responsible for allergies and asthma, making TH2 differentiation of additional medical interest.


Immunology_Janeway

Immunology_Janeway. The third major effector subset of CD4 T cells is TH17. TH17 cells are typically induced in response to extracellular bacteria and fungi, and amplify neutrophilic responses that help to clear such pathogens (see Fig. 9.30). TH17, or type 3, responses also promote B-cell class switching to opsonizing IgG2 and IgG3 antibodies. Cytokines produced by TH17 cells, including IL-17 and IL-22, are also important in activating barrier epithelial cells in the gastrointestinal, respiratory, and urogenital tracts and the skin, to produce antimicrobial peptides that resist microbial invasion.


Immunology_Janeway

Immunology_Janeway. In contrast to TH1, TH2, or TH17 cells, TFH cells contribute to the eradication of most classes of pathogens through their unique role in providing help to B cells to promote germinal center responses—irrespective of the pattern of immune response with which they are associated. Thus, TFH cells are elicited in the context of either type 1, type 2, or type 3 responses, where they play a central role in the development of distinct patterns of class-switched antibodies. TFH cells are identified mainly by their expression of certain markers, such as CXCR5 and PD-1, and their localization to lymphoid follicles.


Immunology_Janeway

Immunology_Janeway. Prior to the discovery of TFH cells, a point of controversy had been the role of CD4 T effector subsets in providing B-cell help. Although it was originally implied that this was primarily the function of TH2 cells, it is now thought that the TFH cell, rather than TH1, TH2, or TH17 cells, is the primary effector T cell that provides B-cell help for high-affinity antibody production in lymphoid follicles. Nevertheless, TFH cells develop as a component of type 1, 2, or 3 responses, and share production of some of the same lineage-defining cytokines of TH1, TH2, and TH17 cells to drive the differentiation of naive B cells to alternative patterns of isotype switching. This explains how, in the course of an infection, B cells can receive help to switch to IgE through the presence of ‘TH2’ cytokines, or switch to other isotypes such as IgG2a through the presence of ‘TH1’ cytokines. Thus, while the developmental relationship of TFH to other CD4 subsets is still a matter of active research,


Immunology_Janeway

Immunology_Janeway. or switch to other isotypes such as IgG2a through the presence of ‘TH1’ cytokines. Thus, while the developmental relationship of TFH to other CD4 subsets is still a matter of active research, TFH cells appear to represent a distinct branch of effector T cells that remain within the lymphoid tissues and are specialized for providing B-cell help. We will return to the helper functions of TFH cells in more detail in Chapters 10 and 11.


Immunology_Janeway

Immunology_Janeway. All the effector T cells described above are involved in activating their target cells to make responses that help clear pathogens from the body. Other CD4 T cells have a different function. These are called regulatory T cells, or Treg cells, because their function is to suppress T-cell responses rather than activate them. Thus, Treg cells are involved in limiting the immune response and preventing autoimmunity. Two main subsets of regulatory T cells are currently recognized. One subset becomes committed to a regulatory fate while still in the thymus, and is known as natural, or thymically derived, T cells (nT and tT , respectively; see Section 8-26). The other subset of T cells differenti ates from naive CD4 T cells in the periphery under the influence of particular environmental conditions. This group is known as induced, or peripherally derived, T cells (iT and pT , respectively). These cells will be discussed further in Section 9-23.


Immunology_Janeway

Immunology_Janeway. 9-21 Cytokines induce the differentiation of naive CD4 T cells down distinct effector pathways.


Immunology_Janeway

Immunology_Janeway. Having briefly noted the types and functions of CD4 T-cell subsets, we will now consider how they are derived from naive T cells. The fate of the progeny of a naive CD4 T cell is largely defined during the initial priming period and is regulated by signals provided by the local environment, whether by the priming antigen-presenting cell or other innate immune cells that have been activated by a pathogen. As noted previously, the principal determinants of the developmental fate of naive CD4 T cells are the combination and balance of lineage-specifying cytokines, which are integrated with TCR and co-stimulatory signaling during priming. The five main subsets into which naive CD4 T cells may develop—TH1, TH2, TH17, TFH, and induced regulatory T cells (iTreg cells)—are associated with distinct signals that induce their formation, different transcription factors that drive their differentiation, and unique cytokines and surface markers that define their identity (Figs. 9.31 and 9.32).


Immunology_Janeway

Immunology_Janeway. TH1 development is induced when there is a predominance of the cytokines IFN-γand IL-12 during the early stages of naive T-cell activation. As described in Section 3-16, many key cytokines, including IFN-γ and IL-12, stimulate the JAK–STAT intracellular signaling pathway, resulting in the activation of specific gene networks. Different members of the JAK and STAT families are activated by different cytokines. Each of the effector pathways is dependent on a distinct pattern of STAT activation downstream of the lineage-specifying cytokines to program a unique transcription factor network that defines the gene-expression profile of mature effector T cells (see Fig. 9.32). For TH1 development, STAT1 and STAT4 are critical and are sequentially activated by interferons (type 1—IFN-α and IFN-β; or type 2—IFN-γ) and IL-12, respectively, which are produced by innate immune cells early during infection. Activated group 1 ILCs, such as NK cells, may also be an important source of IFN-γ. Finally,


Immunology_Janeway

Immunology_Janeway. type 2—IFN-γ) and IL-12, respectively, which are produced by innate immune cells early during infection. Activated group 1 ILCs, such as NK cells, may also be an important source of IFN-γ. Finally, TH1 cells themselves may provide IFN-γ, thus reinforcing the signal for the differentiation of more TH1 cells through a positive feedback loop.


Immunology_Janeway

Immunology_Janeway. Fig. 9.31 Cytokines are the principal determinants of alternative programs of CD4 T-cell effector differentiation.


Immunology_Janeway

Immunology_Janeway. antigen-presenting cells, principally dendritic cells, as well as other innate immune cells can provide various cytokines that induce the development of naive Cd4 T cells into distinct subsets. The environmental conditions, such as the exposure to various pathogens, determine which cytokines innate sensor cells will produce. Th1 cells differentiate in response to sequential IFn-γ and IL-12 signaling, whereas Th2 cells differentiate in response to IL-4. IL-6 produced by dendritic cells acts with transforming growth factor-β (TGF-β) to induce differentiation of Th17 cells, which upregulate expression of the IL-23 receptor and become responsive to IL-23. TFh cells also require IL-6 for their development, although it is not currently understood what additional signals might induce their differentiation from naive precursors. When pathogens are absent, the presence of TGF-β and IL-2, and the lack of IL-6, favor the development of induced T cells.


Immunology_Janeway

Immunology_Janeway. Fig. 9.32 Different members of the STAT family of transcription factors act immediately downstream of cytokines that determine CD4 T-cell subset development. With the exception of TGF-β, which participates in both Th17 and iTreg development, each of the cytokines that specify the development of distinct effector cells activates different members of the sTaT family of transcription factors. Th1 cell differentiation is dependent on sequential activation of sTaT1 and sTaT4 by binding of IFn-γ and IL-12 to their respective receptors on antigen-activated naive Cd4 T cells. Both of these sTaT factors participate in the induction of T-bet expression, which then cooperates with the sTaTs to program Th1 differentiation. Th2 cell differentiation is dependent on sTaT6 activation downstream of IL-4 receptor signaling. sTaT6 acts to increase GaTa3 expression, which cooperates with sTaT6 to program Th2 differentiation. IL-6 activates sTaT3, which, in concert with TGF-β, participates in the


Immunology_Janeway

Immunology_Janeway. IL-4 receptor signaling. sTaT6 acts to increase GaTa3 expression, which cooperates with sTaT6 to program Th2 differentiation. IL-6 activates sTaT3, which, in concert with TGF-β, participates in the induction of rorγt expression and Th17 differentiation. IL-23, which acts later in Th17 differentiation, also activates sTaT3 to sustain and amplify the Th17 program. The programming of TFh cell differentiation by sTaT factors is not fully understood, although sTaT3 actions upstream of Bcl-6 expression are essential. activation of sTaT5 by IL-2 is important in iTreg differentiation and acts upstream of Foxp3 expression.


Immunology_Janeway

Immunology_Janeway. The activation of STAT1 by interferon induces in activated naive CD4 T cells induces the expression of another transcription factor, T-bet, which switches on the genes for IFN-γ and the inducible component of the IL-12 receptor, IL-12Rβ2 (the other component of the receptor, IL-12Rβ1, is already expressed on naive T cells). These T cells are now committed to becoming TH1 cells, and can be further activated by IL-12 produced by dendritic cells and macrophages to induce STAT4 signaling. STAT4 further upregulates T-bet expression and completes TH1 programming. Due to its central role in programming TH1 development, T-bet is sometimes referred to as a ‘master regulator’ of TH1 cell differentiation.


Immunology_Janeway

Immunology_Janeway. TH2 development requires IL-4. When an antigen-activated naive T cell encounters IL-4, its receptor activates STAT6, which promotes expression of the transcription factor GATA3. GATA3 is a powerful activator of the genes encoding several cytokines produced by TH2 cells, such as IL-4 and IL-13. GATA3 also induces its own expression, thereby stabilizing TH2 differentiation via cell-intrinsic positive feedback. The initial source of IL-4 that triggers a TH2 response has long been debated. Eosinophils, basophils, and mast cells are each attractive possibilities because they can produce abundant IL-4 when activated by chitin, a polysaccharide present in helminth parasites, as well as in insects and crustaceans, which induces TH2 responses. In mice treated with chitin, eosinophils and basophils are recruited into tissues and are activated to produce IL-4. In humans, group 2 ILCs can also produce IL-4, suggesting that these cells might contribute to TH2 differentiation, although this is


Immunology_Janeway

Immunology_Janeway. are recruited into tissues and are activated to produce IL-4. In humans, group 2 ILCs can also produce IL-4, suggesting that these cells might contribute to TH2 differentiation, although this is unproven. Clearly, there are several innate immune cells that might contribute IL-4 for TH2 development, and the cellular source might differ, contingent on the inciting antigen. Similar to the positive feedback for TH1 cell development provided by IFN-γ produced by activated TH1 cells, IL-4 produced by activated TH2 cells may amplify TH2 development from naive T-cell precursors.


Immunology_Janeway

Immunology_Janeway. TH17 cells arise when the cytokines IL-6 and transforming growth factor (TGF)-β predominate during naive CD4 T-cell activation (see Figs. 9.31 and 9.32). Development of TH17 cells requires the actions of STAT3, which is activated by IL-6 signaling. Developing TH17 cells express the receptor for the cytokine IL-23, rather than the IL-12 receptor typical of TH1 cells, and the expansion and further development of TH17 effector activity seem to require IL-23, similar to the requirement for IL-12 in effective TH1 responses (see Figs.


Immunology_Janeway

Immunology_Janeway. 9.31 and 9.32). The signature transcription factor, or master regulator, of TH17 cell differentiation is RORγt, a nuclear hormone receptor that is central to stabilizing the development of TH17 cells. The source of IL-6 and TGF-β required for TH17 cell differentiation is primarily derived from innate immune cells activated by microbial products. Unlike TH1 or TH2 cells, TH17 cells do not appear to directly induce further TH17 cell development from naive CD4 T cells via positive feedback, as they do not produce IL-6. However, IL-17 produced by TH17 cells appears to enhance IL-6 production by innate immune cells and provide an indirect mechanism for reinforcing TH17 differentiation from naive precursors.


Immunology_Janeway

Immunology_Janeway. upon antigen recognition in secondary lymphoid tissues, and not the thymus. They develop when naive T cells are activated in the presence of the cytokine transforming growth factor-β (TGF-β) and in the absence of IL-6 and other pro-inflammatory cytokines. Thus, it is the presence or absence of IL-6 that determines whether TGF-β co-signaling leads to the development of immunosuppressive Treg cells or of TH17 cells, which promote inflammation and the generation of immunity (Fig. 9.33). The generation of IL-6 by innate immune cells is regulated by the presence or absence of pathogens, with pathogen products tending to stimulate its production. In the absence of pathogens, IL-6 production is low, favoring differentiation of the immunosuppressive Treg cells and so preventing unwanted immune responses. Like nT cells, iT cells are distinguished by expression of the transcription factor FoxP3 and cell-surface CD25, and appear to be functionally equivalent to nT cells. Both iT and nT cells


Immunology_Janeway

Immunology_Janeway. responses. Like nT cells, iT cells are distinguished by expression of the transcription factor FoxP3 and cell-surface CD25, and appear to be functionally equivalent to nT cells. Both iT and nT cells themselves can produce TGF-β, as well as IL-10, which act in an inhibitory manner to suppress immune responses and inflammation, and may act to support further iTreg differentiation.


Immunology_Janeway

Immunology_Janeway. TFH cells, unlike the subsets described above, have not been produced efficiently in vitro, and so the requirements for their differentiation are not yet clearly established. IL-6 seems to be important for TFH development, but much remains to be learned about the control of this subset. One transcription factor important for TFH development is Bcl-6, which is required for the expression of CXCR5, the receptor for the chemokine CXCL13, which is produced by the stromal cells of the B-cell follicle. CXCR5 is essential for TFH localization in follicles, and is not expressed by other effector T-cell subsets. TFH cells also express ICOS, the ligand for which is expressed abundantly by B cells. ICOS seems crucial for the helper activity of TFH cells, because mice lacking ICOS show a severe defect in T-cell-dependent antibody responses. In addition to production of low amounts of cytokines characteristic of the effector T-cell subsets with which they develop in parallel (for example, IFN-γ,


Immunology_Janeway

Immunology_Janeway. in T-cell-dependent antibody responses. In addition to production of low amounts of cytokines characteristic of the effector T-cell subsets with which they develop in parallel (for example, IFN-γ, IL-4, or IL-17), and which promote different patterns of B-cell class switching, TFH cells produce high amounts of IL-21, a cytokine that supports the proliferation and differentiation of B cells into antibody-producing plasma cells.


Immunology_Janeway

Immunology_Janeway. 9-22 CD4 T-cell subsets can cross-regulate each other’s differentiation through the cytokines they produce.


Immunology_Janeway

Immunology_Janeway. The various subsets of effector CD4 T cells each have very different functions. For the immune response to efficiently control different types of pathogens it must orchestrate a coordinated effector response that is dominated by one of these subsets. A principal means of achieving this is through the distinct ensemble of cytokines that are produced by the different subsets. Importantly, some of these same cytokines also participate in positive and negative feedback loops that control the differentiation of effector T cells from naive precursors, thereby providing a mechanism to promote one pattern of effector response while suppressing others. For example, both IFN-γ (produced by TH1 cells) and IL-4 (produced by TH2 cells) potently inhibit TH17 development, promoting TH1 or TH2 development, respectively (Fig. 9.34). Similarly, there is cross-regulation between TH1 and TH2 cells. IL-4 produced by TH2 cells potently inhibits TH1 development. Conversely, IFN-γ, a product of TH1 cells,


Immunology_Janeway

Immunology_Janeway. respectively (Fig. 9.34). Similarly, there is cross-regulation between TH1 and TH2 cells. IL-4 produced by TH2 cells potently inhibits TH1 development. Conversely, IFN-γ, a product of TH1 cells, can inhibit the proliferation of TH2 cells (see Fig. 9.34). TGF-β produced by T cells inhibits the development of both TH1 and TH2 cells. In this way, cytokines produced by effector T cells reinforce the differentiation of their own kind from naive precursor cells.


Immunology_Janeway

Immunology_Janeway. TH1 cells generate copious amounts of IFN-γ when they recognize antigen on a target cell, thus reinforcing the signal for the differentiation of more TH1 cells through a positive feedback loop. In this way, recognition of a particular type


Immunology_Janeway

Immunology_Janeway. Fig. 9.33 A shared requirement for TGF-β in the differentiation of iTreg and TH17 cells provides a developmental link that reflects their complementary roles in promoting mutualism with the microbiota. a major site for the deployment of iT and Th17 cells is mucosal tissues, particularly the intestines, where the immune system must cope with an extraordinarily high density of microbial organisms that comprise the microbiota. While the microbiota provides its host with important metabolic functions, it also represents a potential threat as some of its constituents are opportunistic pathogens that can cause serious infections if they breach the mucosal barrier. as an adaptation to restrain untoward inflammation directed against the microbiota while retaining the capacity to mount a host-protective immune response should barrier breach occur, the developmental balance between iTreg cells, which suppress inflammatory responses against the microbiota, and Th17 cells, which promote


Immunology_Janeway

Immunology_Janeway. host-protective immune response should barrier breach occur, the developmental balance between iTreg cells, which suppress inflammatory responses against the microbiota, and Th17 cells, which promote host-protective inflammatory responses, is determined by the balance between production of the vitamin a metabolite all-trans retinoic acid (at-ra) and production of the pro-inflammatory cytokine IL-6 by mucosal dendritic cells. at homeostasis, antigens derived from the microbiota are presented by a specialized subset of resident dendritic cells that produce at-ra, but no IL-6. however, when antigens are recognized in the context of TLr-stimulating signals, at-ra production is suppressed in favor of IL-6, thereby favoring the development of Th17 effector cells.


Immunology_Janeway

Immunology_Janeway. under homeostatic conditions, TGF-β produced by T cells represses Th1 and Th2 responses in order to promote T development. under inflammatory conditions that favor IL-6 production, TGF-β production by T cells similarly inhibits the activation of Th1 or Th2 responses (upper panels) in order to facilitate the development of Th17 cells, which otherwise would be potently inhibited by IFn-γ or IL-4. Conversely, if signals are present to induce Th1 or Th2 cells, the cytokines IFn-γ or IL-4 produced by them can override the effect of IL-6 and inhibit Th17 development (lower center panel). IFn-γ produced by Th1 cells blocks the growth of Th2 cells (right panels). on the other hand, IL-4 produced by Th2 cells dominantly prevents Th1 cell development in favor of Th2 (left panels). although not shown, all T-cell subsets can produce IL-10 under conditions of chronic antigen stimulation, which inhibits the production of IL-12, IL-4, and IL-23 by dendritic cells and macrophages, thereby suppressing


Immunology_Janeway

Immunology_Janeway. all T-cell subsets can produce IL-10 under conditions of chronic antigen stimulation, which inhibits the production of IL-12, IL-4, and IL-23 by dendritic cells and macrophages, thereby suppressing the development and/or maintenance of Th1, Th2, and Th17 cells.


Immunology_Janeway

Immunology_Janeway. Fig. 9.34 The subsets of CD4 T cells each produce cytokines that can negatively regulate the development or effector activity of other subsets. IL-4 or IFN-˜can inhibit development of TH17 cells IL-4IFN-˜TH17IL-4IFN-˜IL-4 acts to inhibit differentiation of TH1 cells IFN-˜acts on TH2 cells to inhibit proliferation TH1TH2IL-4TGF-°TGF-°IFN-˜IFN-˜Activated TH2 cells secrete IL-4 Activated TH1 cells secrete IFN-˜TH2TregTH1Treg cells suppress the differentiation and proliferation of TH1 and TH2 cells of pathogen by the innate immune system initiates a chain reaction that links the innate response to the adaptive immune response, which in turn amplifies the innate response. Thus, certain intracellular bacterial infections (for example, mycobacteria and Listeria) induce dendritic cells and macrophages to produce IL-12, favoring the emergence of TH1 effector cells. TH1 cells, in turn, promote enhanced macrophage activation that clears these intracellular pathogens.


Immunology_Janeway

Immunology_Janeway. The adverse consequences of inappropriate cross-regulation of effector T-cell responses by cytokines have been demonstrated in a number of infectious models in mice. Such studies reinforce the notion that induction of the appropriate effector CD4 T-cell subset is crucial for pathogen clearance, and show that subtle differences in CD4 T-cell responses can have a significant impact on the outcome of infection. One example of this is the murine model of infection by the protozoan parasite Leishmania major, which requires a TH1 response and activation of macrophages for clearance. C57BL/6 mice produce TH1 cells that protect the animal by activating infected macrophages to kill


Immunology_Janeway

Immunology_Janeway. L. major. In BALB/c mice infected with L. major, however, CD4 T cells fail to differentiate into TH1 cells; instead, they become TH2 cells, which are unable to activate macrophages to inhibit Leishmania growth. This difference seems to result from a population of memory T cells that are specific for gut-derived antigens but cross-react with an antigen, LACK (Leishmania analog of the receptors of activated C kinase), expressed by the Leishmania parasite. These memory cells are present in both strains of mice, but for unknown reasons they produce IL-4 in BALB/c mice but not in C57BL/6 mice. In BALB/c mice, the small amount of IL-4 secreted by these memory cells during Leishmania infection drives new Leishmania-specific CD4 T cells to become TH2 cells instead of TH1 cells, leading to failure of pathogen elimination and death. The preferential development of TH2 rather than TH1 cells in BALB/c mice can be reversed if IL-4 is blocked early during infection by anti-IL-4 antibody, but this


Immunology_Janeway

Immunology_Janeway. of pathogen elimination and death. The preferential development of TH2 rather than TH1 cells in BALB/c mice can be reversed if IL-4 is blocked early during infection by anti-IL-4 antibody, but this treatment is ineffective after a week or so of infection, demonstrating the crucial importance of cytokines early in developmental decisions made by naive T cells (Fig. 9.35).


Immunology_Janeway

Immunology_Janeway. 9-23 Regulatory CD4 T cells are involved in controlling adaptive immune responses. Regulatory T cells play a central role in preventing autoreactive immune responses and fall into different groups that are defined by their different developmental origins and functions. Natural T-regulatory (nT ) cells develop in the thymus (see Section 8-26) and are CD4-positive cells that constitutively express CD25 and high levels of the L-selectin receptor CD62L and of CTLA-4. Induced T (iT ) cells arise in the periphery from naive CD4 T cells and also express CD25 and CTLA-4 (see Section 9-20). Collectively, T cells represent about 5–10% of the CD4 T cells in circuation. A hallmark of both natural and induced T cells is expression of the transcription factor FoxP3, which, among other actions, interferes with the interaction between AP-1 and NFAT at the IL-2 gene promoter, preventing transcriptional activation of the gene and production of IL-2.


Immunology_Janeway

Immunology_Janeway. ventional α:β T-cell receptors and are selected in the thymus by high-affinity binding to MHC molecules containing self-peptides. It is not currently known whether they are activated to express their regulatory function in the periphery by the same self ligands that selected them in the thymus or by other self or non-self antigens. Multiple mechanisms appear to contribute to the ability of T cells to inhibit responses of other T cells, but principal among these are interactions with antigen-presenting cells that interfere with the capacity of antigen-presenting cells to provide activating signals. The expression of high levels of CTLA-4 on the surface of natural T cells is thought to permit them to compete for B7 expressed by antigen-presenting cells, thereby preventing adequate co-stimulation of naive T cells. Indeed, it has been proposed that CTLA4 expressed on T cells can physically remove B7 molecules from the surface of antigen-presenting cells, thereby depleting them of


Immunology_Janeway

Immunology_Janeway. of naive T cells. Indeed, it has been proposed that CTLA4 expressed on T cells can physically remove B7 molecules from the surface of antigen-presenting cells, thereby depleting them of co-stimulatory activity. Similarly, by expressing CD25, and thus the high-affinity receptor for IL-2, and lacking the ability to produce IL-2, T cells appear to sequester IL-2 from naive T cells, which lack CD25 expression until fully activated.


Immunology_Janeway

Immunology_Janeway. Other functions of T cells are mediated by their production of immunosup pressive cytokines. TGF-β produced by T cells can inhibit T-cell prolifera tion (see Fig. 9.34). IL-10, which is produced by T cells late in an immune response, inhibits the expression of MHC molecules and co-stimulatory molecules by antigen-presenting cells. As a means of limiting the responses of effector T cells, IL-10 also inhibits the production of pro-inflammatory cytokines by antigen-presenting cells. For example, IL-10 potently inhibits the production of IL-12 and IL-23 by antigen-presenting cells and thus impairs their ability to promote the differentiation and maintenance of TH1 and TH17 cells, respectively. The critical role of T cells in immune regulation is highlighted by several autoimmune syndromes (described in Chapter 15) that are caused by deficiency in different aspects of T cell function.


Immunology_Janeway

Immunology_Janeway. Although they differentiate in secondary lymphoid tissues after export from the thymus, induced T cells also express FoxP3 and share most of the phenotypic and functional features of natural T cells. A major function of iT cells is the prevention of inflammatory immune responses to the commensal microbiota, particularly microbes resident in mucosal tissues such as the intestines. Here, iT cells appear to be the dominant source of IL-10, deficiency of which causes inflammatory bowel disease, an immune-mediated disease of the intestines characterized by chronic reactivity against antigens of the intestinal microbiota (see also Section 15-23). As will be discussed in more detail in Chapter 12, the differentiation of induced T cells in the intestines is favored by the presence of antigen-presenting cells that produce retinoic acid, which is derived from vitamin A. Retinoic acid produced by intestinal dendritic cells acts with TGF-β to induce T differentiation while suppressing the


Immunology_Janeway

Immunology_Janeway. cells that produce retinoic acid, which is derived from vitamin A. Retinoic acid produced by intestinal dendritic cells acts with TGF-β to induce T differentiation while suppressing the differentiation of TH17 cells (see Fig. 9.33). The antagonistic balance of retinoic acid and IL-6 therefore


Immunology_Janeway

Immunology_Janeway. Fig. 9.35 The development of CD4 T-cell subsets can be manipulated by altering the cytokines acting during the early stages of infection. elimination of infection with the intracellular protozoan parasite Leishmania major requires a Th1 response, because IFn-γ is needed to activate the macrophages that provide protection. BaLB/c mice are normally susceptible to L. major because they generate a Th2 response to the pathogen. This is because they produce IL-4 early during infection and this induces naive T cells to develop into the Th2 lineage (see the text). Treatment of BaLB/c mice with neutralizing anti-IL-4 antibodies at the beginning of infection inhibits this IL-4 and prevents the diversion of naive T cells toward the Th2 lineage; these mice develop a protective Th1 response. controls the differentiation of induced Treg cells and TH17 cells, respectively, in the intestinal mucosa-associated lymphoid tissues (MALT).


Immunology_Janeway

Immunology_Janeway. controls the differentiation of induced Treg cells and TH17 cells, respectively, in the intestinal mucosa-associated lymphoid tissues (MALT). CD4 T cells that lack FoxP3 expression but produce immunosuppressive cytokines characteristic of Treg cells have also been described. One such population, referred to as TR1 cells, has been defined largely by their production of IL-10, but absence of expression of FoxP3. However, we now recognize that many different cells, including TH1, TH2, TH17, and B cells, can produce IL-10 under certain circumstances, such as during chronic responses to persistent antigen. Therefore, it is uncertain whether TR1 cells represent a distinct subset of T cells, and if so, whether they have unique functions in immune regulation. Summary.


Immunology_Janeway

Immunology_Janeway. Summary. The crucial first step in adaptive immunity is the activation, or priming, of naive antigen-specific T cells by antigen-presenting cells within the lymphoid tissues through which they constantly circulate. The most distinctive feature of antigen-presenting cells is the expression of cell-surface co-stimulatory molecules, of which the B7 molecules are the most important. Naive T cells will respond to antigen only when the antigen-presenting cell presents both a specific antigen to the T-cell receptor and a B7 molecule to CD28 on the T cell. This dual requirement for both receptor ligation and co-stimulation by the same antigen-presenting cell helps to prevent naive T cells from responding to self antigens on tissue cells, which lack co-stimulatory activity.


Immunology_Janeway

Immunology_Janeway. Activation of naive T cells leads to their proliferation and differentiation into effector T cells, the critical event in most adaptive immune responses. Various combinations of cytokines regulate the type of effector T cell that develops in response to antigen. In turn, the cytokines present during primary T-cell activation are influenced by the innate immune system. Once an expanded clone of T cells acquires effector function, its progeny can act on any target cell that displays antigen on its surface. Effector T cells have a variety of functions. CD8 cytotoxic T cells recognize virus-infected cells and kill them. TH1 effector cells promote the activation of macrophages to enhance their killing of intracellular pathogens. TH2 cells promote mucosal barrier immunity against pathogens, such as helminths, requiring the effector activities of cells such as eosinophils and mast cells for their elimination. The elimination of certain types of bacteria and fungi is orchestrated by TH17


Immunology_Janeway

Immunology_Janeway. such as helminths, requiring the effector activities of cells such as eosinophils and mast cells for their elimination. The elimination of certain types of bacteria and fungi is orchestrated by TH17 cells, particularly at barrier sites, where they recruit neutrophils to sites of infection and promote the production of antimicrobial peptides by epithelial cells. TFH cells are specialized for interactions with B cells and localization to the B-cell follicle and germinal centers, where they provide help for antibody production and isotype switching. Regulatory CD4 T-cell subsets restrain the immune response by preventing the activation of self-reactive naive T cells by antigen-presenting cells and producing inhibitory cytokines that limit the effector responses of other T-cell subsets.


Immunology_Janeway

Immunology_Janeway. General properties of effector T cells and their cytokines. T-cell effector functions involve the interaction of an effector T cell with a target cell displaying specific antigen. Effector proteins expressed by the T cell, whether cell-associated (for example, CD40L) or secreted (for example, cytokines), are focused on the target by mechanisms that are activated by antigen recognition. The focusing mechanism is common to all types of effector T cells, whereas their effector actions depend on the type of effector T cell that is engaged. 9-24 Effector T-cell interactions with target cells are initiated by antigen-nonspecific cell-adhesion molecules.


Immunology_Janeway

Immunology_Janeway. Once an effector T cell has completed its differentiation in the lymphoid tissue, it must find target cells that are displaying the peptide:MHC complex that it recognizes. TFH cells encounter their B-cell targets without leaving the lymphoid tissue. However, most other effector T cells emigrate from their site of activation in lymphoid tissues and enter the blood, either directly if primed by antigen in the spleen or via the efferent lymphatics and thoracic duct if primed in lymph nodes. Because of the cell-surface changes that have occurred during their differentiation, effector T cells can now migrate into tissues, particularly at sites of infection. They are guided to these sites by changes in the adhesion molecules expressed on the endothelium of the local blood vessels as a result of infection, and by local chemotactic factors, as will be discussed further in Chapter 11.


Immunology_Janeway

Immunology_Janeway. The initial binding of an effector T cell to its target, like that of a naive T cell to an antigen-presenting cell, is an antigen-nonspecific interaction mediated by LFA-1 and CD2. The levels of LFA-1 and of CD2 are twoto fourfold higher on effector T cells than on naive T cells, and so effector T cells can bind efficiently to target cells that have less ICAM and CD58 on their surface than do antigen-presenting cells. This interaction is transient unless recognition of antigen on the target cell by the T-cell receptor triggers an increase in the affinity of the T-cell’s LFA-1 for its ligands. The T cell then binds more tightly to its target and remains bound long enough to release its effector molecules. Effector CD4 T cells, which activate macrophages or induce B cells to secrete antibody, have to switch on new genes and synthesize new proteins to carry out their effector actions and so must maintain contact with their targets for relatively long periods. Cytotoxic T cells, by


Immunology_Janeway

Immunology_Janeway. have to switch on new genes and synthesize new proteins to carry out their effector actions and so must maintain contact with their targets for relatively long periods. Cytotoxic T cells, by contrast, can be observed under the microscope attaching to and dissociating from successive targets relatively rapidly as they kill them (Fig. 9.36). Killing of the target, or some local change in the T cell, allows the effector T cell to detach and address new targets. How CD4 effector T cells disengage from their antigen-negative targets is not known, although evidence suggests that CD4 binding to MHC class II molecules without engagement of the T-cell receptor provides a signal for the cell to detach.


Immunology_Janeway

Immunology_Janeway. their targets to regulate signaling and to direct the release of effector molecules. When binding to their specific antigenic peptide:self MHC complexes or to self peptide:self MHC complexes, the T-cell receptors and their associated co-receptors cluster at the site of cell–cell contact, forming what is called the supramolecular activation complex (SMAC) or the immunological synapse. Other cell-surface molecules also cluster here. For example, the


Immunology_Janeway

Immunology_Janeway. Fig. 9.36 Interactions of T cells with their targets initially involve nonspecific adhesion molecules. The major initial interaction is between LFa-1 on the T cell, illustrated here as a cytotoxic Cd8 T cell, and ICaM-1 or ICaM-2 on the target cell (top panel). This binding allows the T cell to remain in contact with the target cell and to scan its surface for the presence of specific peptide:MhC complexes. If the target cell does not carry the specific antigen, the T cell disengages (second panel) and can scan other potential targets until it finds the specific antigen (third panel). signaling through the T-cell receptor increases the strength of the adhesive interactions, prolonging the contact between the two cells and stimulating the T cell to deliver its effector molecules. The T cell then disengages (bottom panel). Chapter 9: T-Cell-Mediated Immunity


Immunology_Janeway

Immunology_Janeway. Chapter 9: T-Cell-Mediated Immunity Outer ring (red) pSMAC LFA-1:ICAM-1 talin TCR, CD4, CD28 peptide:MHC CD8, PKC-˜Inner circle (green) cSMAC Organization of the immunological synapse T cell dendritic cell pSMAC cSMAC


Immunology_Janeway

Immunology_Janeway. Fig. 9.37 The area of contact between an effector T cell and another cell forms an immunological synapse. a confocal fluorescence micrograph of the area of contact between a Cd4 T cell and an antigen-presenting cell (apC) (as viewed through one of the cells) is shown. proteins in the contact area between the T cell and the apC form a structure called the immunological synapse, also known as the supramolecular activation complex (sMaC), which is organized into two distinct regions: the outer, or peripheral sMaC (psMaC), indicated by the red ring; and the inner, or central sMaC (csMaC), indicated in bright green. The csMaC is enriched in the T-cell receptor (TCr), Cd4, Cd8, Cd28, Cd2, and pKC-ε. The psMaC is enriched for the integrin LFa-1 and the cytoskeletal protein talin. photograph courtesy of a. Kupfer.


Immunology_Janeway

Immunology_Janeway. tight binding of LFA-1 to ICAM-1 induced by ligation of the T-cell receptor creates a molecular seal that surrounds the T-cell receptor and its co-receptor (Fig. 9.37). In some cases, the contact surface organizes into two zones: a central zone known as the central supramolecular activation complex (cSMAC) and an outer zone known as the peripheral supramolecular activation complex (pSMAC). The cSMAC contains most of the signaling proteins known to be important in T-cell activation. The pSMAC is notable mainly for the presence of the LFA-1 and the cytoskeletal protein talin, which connects LFA-1 to the actin cytoskeleton (see Section 3-18). The immunological synapse is not a static structure as implied by Fig. 9.37, but is quite dynamic. T-cell receptors move from the periphery into the cSMAC, where they undergo endocytosis through ubiquitin-mediated degradation involving the E3 ligase Cbl (see Section 7-5). Because T-cell receptors are being degraded in the cSMAC, signaling is


Immunology_Janeway

Immunology_Janeway. the cSMAC, where they undergo endocytosis through ubiquitin-mediated degradation involving the E3 ligase Cbl (see Section 7-5). Because T-cell receptors are being degraded in the cSMAC, signaling is actually weaker there than in the peripheral contact areas, where microclusters of T-cell receptors are being formed and are highly active (see Section 7-8).


Immunology_Janeway

Immunology_Janeway. Clustering of the T-cell receptors signals a reorientation of the cytoskeleton that polarizes the effector cell and focuses the release of effector molecules at the site of contact with the target cell. This is illustrated for a cytotoxic T cell in Fig. 9.38. An important intermediary in the effect of T-cell signaling on the cytoskeleton is the Wiskott–Aldrich syndrome protein (WASp), defects in which result in the inability of T cells to become polarized, among other effects, and cause an immune deficiency syndrome for which the protein is named (see Sections 7-19 and 13-6). Activation and recruitment of WASp by T-cell receptor signaling is mediated by the adaptor protein Vav (see Section 7-19). Polarization starts with the local reorganization of the cortical actin cytoskeleton at the site of contact; this in turn leads to the reorientation of the microtubule-organizing center (MTOC), the center from which the microtubule cytoskeleton is produced, and reorientation of the Golgi


Immunology_Janeway

Immunology_Janeway. site of contact; this in turn leads to the reorientation of the microtubule-organizing center (MTOC), the center from which the microtubule cytoskeleton is produced, and reorientation of the Golgi apparatus (GA), through which most proteins destined for secretion travel. In the cytotoxic T cell, the cytoskeletal reorientation focuses exocytosis of the preformed cytotoxic granules at the site of T-cell contact with its target cell. The polarization of a T cell also focuses the secretion of newly synthesized effector molecules induced by ligation of the T-cell receptor. For example, the secreted cytokine IL-4, which is the principal effector molecule of TH2 cells, is confined and concentrated at the site of contact with the target cell.


Immunology_Janeway

Immunology_Janeway. Thus, the T-cell receptor controls the delivery of effector signals in three ways: it induces tight binding of effector cells to their target cells to create a narrow space in which effector molecules can be concentrated; it focuses delivery of effector molecules at the site of contact by inducing a reorientation of the secretory apparatus of the effector cell; and it triggers the synthesis and/or release of the effector molecules. All these mechanisms contribute to targeting actions of effector molecules onto the cell bearing specific antigen. Effector T-cell activity is thus highly selective for appropriate target cells, even though effector molecules themselves are not antigen-specific. 9-26 The effector functions of T cells are determined by the array of effector molecules that they produce.