Immunology_Janeway

Immunology_Janeway. to its specific receptor on the neutrophil triggers the activation of the integrins LFA-1 and CR3 (Mac-1; not shown). Inflammatory cytokines such as TNF-α are also necessary to induce the expression of adhesion molecules such as ICAM-1 and ICAM-2, the ligands for these integrins, on the vascular endothelium. Tight binding between ICAM-1 and the integrins arrests the rolling and allows the neutrophil to squeeze between the endothelial cells forming the wall of the blood vessel (i.e., to extravasate). The leukocyte integrins LFA-1 and CR3 are required for extravasation and for migration toward chemoattractants. Adhesion between molecules of CD31, expressed on both the neutrophil and the junction of the endothelial cells, is also thought to contribute to extravasation. The neutrophil also needs to traverse the basement membrane; it penetrates this with the aid of a matrix metalloproteinase enzyme, MMP-9, that it expresses at the cell surface. Finally, the neutrophil migrates along a


Immunology_Janeway

Immunology_Janeway. needs to traverse the basement membrane; it penetrates this with the aid of a matrix metalloproteinase enzyme, MMP-9, that it expresses at the cell surface. Finally, the neutrophil migrates along a concentration gradient of chemokines (shown here as CXCL8) secreted by cells at the site of infection. The electron micrograph shows a neutrophil extravasating between endothelial cells. The blue arrow indicates the pseudopod that the neutrophil is inserting between the endothelial cells. Photograph (×5500) courtesy of I. Bird and J. Spragg.


Immunology_Janeway

Immunology_Janeway. of neutrophil-rich blood fractions or by stimulating their production with specific growth factors largely corrects this susceptibility. 3-20 TNF-α is an important cytokine that triggers local containment of infection but induces shock when released systemically.


Immunology_Janeway

Immunology_Janeway. TNF-α acting on endothelial cells stimulates the expression of adhesion molecules and aids the extravasation of cells such as monocytes and neutrophils. Another important action of TNF-αis to stimulate endothelial cells to express proteins that trigger blood clotting in the local small vessels, occluding them and cutting off blood flow. This can be important in preventing the pathogen from entering the bloodstream and spreading through the blood to organs all over the body. The importance of TNF-α in the containment of local infection is illustrated by experiments in which rabbits were infected locally with a bacterium. Normally, the infection would be contained at the site of the inoculation; if, however, an injection of anti-TNF-α antibody was also given to block the action of TNF-α, the infection spread via the blood to other organs. In parallel, the fluid that has leaked into the tissue in the early phases of an infection carries the pathogen, usually enclosed in dendritic cells,


Immunology_Janeway

Immunology_Janeway. infection spread via the blood to other organs. In parallel, the fluid that has leaked into the tissue in the early phases of an infection carries the pathogen, usually enclosed in dendritic cells, via the lymph to the regional lymph nodes, where an adaptive immune response can be initiated.


Immunology_Janeway

Immunology_Janeway. Once an infection has spread to the bloodstream, however, the same mechanisms by which TNF-α so effectively contains local infection instead becomes catastrophic (Fig. 3.32). Although produced as a membrane-associated cytokine, TNF-α can be cleaved by a specific protease, TACE (TNF-α-converting enzyme, which is encoded by the ADAM17 gene), and released from the membrane as a soluble cytokine. The presence of infection in the bloodstream, or sepsis, is accompanied by a massive release of soluble TNF-α from macrophages in the liver, spleen, and other sites throughout the body. The systemic release of TNF-α into the bloodstream causes vasodilation, which leads to a loss of blood pressure and increased vascular permeability; this in turn leads to a loss of plasma volume and eventually to shock, known in this case as septic shock because the underlying cause is a bacterial infection. The TNF-α released in septic shock also triggers blood clotting in small vessels throughout the body—known


Immunology_Janeway

Immunology_Janeway. known in this case as septic shock because the underlying cause is a bacterial infection. The TNF-α released in septic shock also triggers blood clotting in small vessels throughout the body—known as disseminated intravascular coagulation—which leads to the massive consumption of clotting proteins, so that the patient’s blood cannot clot appropriately. Disseminated intravascular coagulation frequently leads to the failure of vital organs such as the kidneys, liver, heart, and lungs, which are quickly compromised by the failure of normal blood perfusion; consequently, septic shock has a very high mortality rate.


Immunology_Janeway

Immunology_Janeway. Mice with defective or no TNF-α receptors are resistant to septic shock but are also unable to control local infection. Mice in which the ADAM17 gene has been selectively inactivated in myeloid cells are also resistant to septic shock, confirming that the release of soluble TNF-αinto the circulation both depends on TACE and is the main factor responsible for septic shock. Blockade of TNF-α activity, either with specific antibodies or with soluble proteins that mimic the receptor, is a successful treatment for several inflammatory disorders, including rheumatoid arthritis. However, these treatments have been found to reactivate tuberculosis in some apparently well patients with evidence of previous infection (as demonstrated by skin test), which is a direct demonstration of the importance of TNF-α in keeping infection local and in check. 3-21 Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the acute-phase response.


Immunology_Janeway

Immunology_Janeway. 3-21 Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the acute-phase response. As well as their important local effects, the cytokines produced by macrophages and dendritic cells have long-range effects that contribute to host defense. One of these is the elevation of body temperature, which is caused Local infection with Systemic infection with Gram-negative bacteria Gram-negative bacteria (sepsis) Macrophages activated to secrete Macrophages activated in the liver and TNF-˜ in the tissue spleen secrete TNF-˜ into the bloodstream Increased release of plasma proteins into Systemic edema causing decreased blood tissue. Increased phagocyte and volume, hypoproteinemia, and neutropenia, lymphocyte migration into tissue. Increased followed by neutrophilia. Decreased blood platelet adhesion to blood vessel wall volume causes collapse of vessels


Immunology_Janeway

Immunology_Janeway. Phagocytosis of bacteria. Local vessel Disseminated intravascular coagulation occlusion. Plasma and cells drain to leading to wasting and multiple local lymph node organ failure Removal of infection DeathAdaptive immunity mainly by TNF-α, IL-1β, and IL-6. These cytokines are termed endogenous pyrogens because they cause fever and derive from an endogenous source rather than from bacterial components such as LPS, which also induces fever and is an exogenous pyrogen. Endogenous pyrogens cause fever by inducing the synthesis of prostaglandin E2 by the enzyme cyclooxygenase-2, the expression of which is induced by these cytokines. Prostaglandin E2 then acts on the hypothalamus, resulting in an increase in both heat production from the catabolism of brown fat and heat retention from vasoconstriction, which decreases the loss of excess heat through the skin. Exogenous pyrogens are able to induce fever by promoting the production of the endogenous pyrogens


Immunology_Janeway

Immunology_Janeway. Induced innate responses to infection. 119


Immunology_Janeway

Immunology_Janeway. Fig. 3.32 The release of TNF-α by macrophages induces local protective effects, but TNF-α can be damaging when released systemically. The panels on the left show the causes and consequences of local release of TNF-α, and the panels on the right show the causes and consequences of systemic release. In both cases TNF-α acts on blood vessels, especially venules, to increase blood flow and vascular permeability to fluid, proteins, and cells, and to increase endothelial adhesiveness for leukocytes and platelets (center row). Local release thus allows an influx of fluid, cells, and proteins into the infected tissue, where they participate in host defense. Later, blood clots form in the small vessels (bottom left panel), preventing spread of infection via the blood, and the accumulated fluid and cells drain to regional lymph nodes, where an adaptive immune response is initiated. When there is a systemic infection, or sepsis, with bacteria that elicit TNF-α production, TNF-α is released into


Immunology_Janeway

Immunology_Janeway. cells drain to regional lymph nodes, where an adaptive immune response is initiated. When there is a systemic infection, or sepsis, with bacteria that elicit TNF-α production, TNF-α is released into the blood by macrophages in the liver and spleen and acts in a similar way on all small blood vessels in the body (bottom right panel). The result is shock, disseminated intravascular coagulation with depletion of clotting factors, and consequent bleeding, multiple organ failure, and frequently death.


Immunology_Janeway

Immunology_Janeway. Fig. 3.33 The cytokines TNF-α, IL-1β, and IL-6 have a wide spectrum of biological activities that help to coordinate the body’s responses to infection. IL-1β, IL-6, and TNF-α activate hepatocytes to synthesize acute-phase proteins, and bone marrow endothelium to release neutrophils. The acute-phase proteins act as opsonins, whereas the disposal of opsonized pathogens is augmented by the enhanced recruitment of neutrophils from the bone marrow. IL-1β, IL-6, and TNF-α are also endogenous pyrogens, raising body temperature, which is believed to help in eliminating infections. A major effect of these cytokines is to act on the hypothalamus, altering the body’s temperature regulation, and on muscle and fat cells, altering energy mobilization to increase the body temperature. At higher temperatures, bacterial and viral replication is less efficient, whereas the adaptive immune response operates more efficiently.


Immunology_Janeway

Immunology_Janeway. and also by directly inducing cyclooxygenase-2 as a consequence of signaling through TLR-4, leading to the production of prostaglandin E2. Fever is generally beneficial to host defense; most pathogens grow better at lower temperatures, whereas adaptive immune responses are more intense at elevated temperatures. Host cells are also protected from the deleterious effects of TNF-α at raised temperatures.


Immunology_Janeway

Immunology_Janeway. The effects of TNF-α, IL-1β, and IL-6 are summarized in Fig. 3.33. One of the most important of these occurs in the liver and is the initiation of a response known as the acute-phase response (Fig. 3.34). The cytokines act on hepatocytes, which respond by changing the profile of proteins that they synthesize and secrete into the blood. In the acute-phase response, blood levels of some proteins go down, whereas levels of others increase markedly. The proteins induced by TNF-α, IL-1β, and IL-6 are called the acute-phase proteins. Several of these are of particular interest because they mimic the action of antibodies, but unlike antibodies they have broad specificity for pathogen-associated molecular patterns and depend only on the presence of cytokines for their production.


Immunology_Janeway

Immunology_Janeway. One acute-phase protein, the C-reactive protein, is a member of the pentraxin protein family, so called because the proteins are formed from five identical subunits. C-reactive protein is yet another example of a multipronged pathogen-recognition molecule, and it binds to the phosphocholine portion of certain bacterial and fungal cell-wall lipopolysaccharides. Phosphocholine is also found in mammalian cell-membrane phospholipids, but it cannot be bound by C-reactive protein. When C-reactive protein binds to a bacterium, it not only is able to opsonize the bacterium but can also activate the complement cascade by binding to C1q, the first component of the classical pathway of complement activation (see Section 2-7). The interaction with C1q involves the collagen-like parts of C1q rather than the globular heads that make contact with pathogen surfaces, but the same cascade of reactions is initiated.


Immunology_Janeway

Immunology_Janeway. Mannose-binding lectin (MBL) is another acute-phase protein; it serves as an innate recognition molecule that can activate the lectin pathway of complement (see Section 2-6). MBL is present at low levels in the blood of healthy individuals, but it is produced in increased amounts during the acute-phase response. By recognizing mannose residues on microbial surfaces, MBL can act as an opsonin that is recognized by monocytes, which do not express the macrophage mannose receptor. Two other proteins with opsonizing properties that are also produced in increased amounts during an acute-phase response are the surfactant proteins, SP-A and SP-D. These are produced by the liver and a variety of epithelia. They are, for example, found along with macrophages in the alveolar fluid of the lung, where they are secreted by


Immunology_Janeway

Immunology_Janeway. Liver Activation of complement Opsonization Bone marrow endothelium Phagocytosis Hypothalamus Decreased viral and bacterial replication Increased antigen processing Increased speciÿc immune response Fat, muscle Dendritic cells Acute-phase proteins (C-reactive protein, mannose-binding lectin) Neutrophil mobilization Increased body temperature Protein and energy mobilization to allow increased body temperature TNF-˜stimulates migration to lymph nodes and maturation Initiation of adaptive immune response IL-1˜/IL-6/TNF-°


Immunology_Janeway

Immunology_Janeway. Fig. 3.34 The acute-phase response produces molecules that bind pathogens but not host cells. Acute-phase proteins are produced by liver cells in response to cytokines released by macrophages in the presence of bacteria (top panel). They include serum amyloid protein (SAP) (in mice but not humans), C-reactive protein (CRP), fibrinogen, and mannose-binding lectin (MBL). CRP binds phosphocholine on certain bacterial and fungal surfaces but does not recognize it in the form in which it is found in host cell membranes (middle panel). SAP and CRP are homologous in structure; both are pentraxins, forming five-membered discs, as shown for SAP (lower panel). SAP both acts as an opsonin in its own right and activates the classical complement pathway by binding C1q to augment opsonization. MBL is a member of the collectin family, which also includes the pulmonary surfactant proteins SP-A and SP-D. Like CRP, MBL can act as an opsonin in its own right, as can SP-A and SP-D. Model structure


Immunology_Janeway

Immunology_Janeway. is a member of the collectin family, which also includes the pulmonary surfactant proteins SP-A and SP-D. Like CRP, MBL can act as an opsonin in its own right, as can SP-A and SP-D. Model structure courtesy of J. Emsley.


Immunology_Janeway

Immunology_Janeway. pneumocytes, and are important in promoting the phagocytosis of opportunistic respiratory pathogens such as Pneumocystis jirovecii (formerly known as P. carinii), one of the main causes of pneumonia in patients with AIDS. Thus, within a day or two, the acute-phase response provides the host with several proteins with the functional properties of antibodies but able to bind a broad range of pathogens. However, unlike antibodies, which we describe in Chapters 4 and 10, acute-phase proteins have no structural diversity and are made in response to any stimulus that triggers the release of TNF-α, IL-1, and IL-6. Therefore, unlike antibodies, their synthesis is not specifically induced and targeted.


Immunology_Janeway

Immunology_Janeway. A final, distant effect of the cytokines produced by macrophages is to induce leukocytosis, an increase in the numbers of circulating neutrophils. The neutrophils come from two sources: the bone marrow, from which mature leukocytes are released in increased numbers; and sites in blood vessels, where they are attached loosely to endothelial cells. Thus the effects of these cytokines contribute to the control of infection while the adaptive immune response is being developed. As shown in Fig. 3.33, TNF-α also has a role in stimulating the migration of dendritic cells from their sites in peripheral tissues to the lymph nodes and in their maturation into nonphagocytic but highly co-stimulatory antigen-presenting cells. 3-22 Interferons induced by viral infection make several contributions to host defense.


Immunology_Janeway

Immunology_Janeway. 3-22 Interferons induced by viral infection make several contributions to host defense. Viral infection induces the production of interferons, originally named because of their ability to interfere with viral replication in previously uninfected tissue culture cells. Interferons have a similar role in vivo, blocking the spread of viruses to uninfected cells. There are numerous genes encoding antiviral, or type I, interferons. Best understood are the IFN-α family of 12 closely related human genes and IFN-β, the product of a single gene; less well studied are IFN-κ, IFN-ε, and IFN-ω. IFN-γ is the sole type II interferon.


Immunology_Janeway

Immunology_Janeway. Type III interferons are a newly classified IFN family composed of the products of three IFN-λ genes, also known as IL-28A, IL-28B, and IL-29, which bind a heterodimeric IFN-λ receptor composed of a unique IL-28Rα subunit and the β subunit of the IL-10 receptor. While receptors for type I interferons and IFN-γ are widespread in their tissue distribution, type III receptors are more restricted, not expressed by fibroblasts or epithelial cells, but expressed on epithelial cells. Type I interferons are inducible and are synthesized by many cell types after infection by diverse viruses. Almost all types of cells can produce IFN-α and IFN-β in response to activation of several innate sensors. For example, type I interferons are induced by RIG-I and MDA-5 (the sensors of cytoplasmic viral RNA) downstream of MAVS, and by signaling from cGAS (the sensor of cytoplasmic DNA) downstream of STING (see Sections 3-10 and 3-11).


Immunology_Janeway

Immunology_Janeway. C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement Serum amyloid protein IFN-˜, IFN-°Virus-infected host cells virus


Immunology_Janeway

Immunology_Janeway. IFN-˜, IFN-°Virus-infected host cells virus Fig. 3.35 Interferons are antiviral proteins produced by cells in response to viral infection. The interferons IFN-α and IFN-β have three major functions. First, they induce resistance to viral replication in uninfected cells by activating genes that cause the destruction of mRNA and inhibit the translation of viral proteins and some host proteins. These include the Mx proteins, oligoadenylate synthetase, PKR, and IFIT proteins. Second, they can induce MHC class I expression in most cell types in the body, thus enhancing their resistance to NK cells; they may also induce increased synthesis of MHC class I molecules in cells that are newly infected by virus, thus making them more susceptible to being killed by CD8 cytotoxic T cells (see Chapter 9). Third, they activate NK cells, which then selectively kill virus-infected cells.


Immunology_Janeway

Immunology_Janeway. However, some immune cells seem to be specialized for this task. In Section 3-1 we introduced the plasmacytoid dendritic cell (pDC). Also called interferon-producing cells (IPCs) or natural interferon-producing cells, human plasmacytoid dendritic cells were initially recognized as rare peripheral blood cells that accumulate in peripheral lymphoid tissues during a viral infection and make abundant type I interferons (IFN-α and IFN-β)—up to 1000 times more than other cell types. This abundant production of type I interferon may result from the efficient coupling of viral recognition by TLRs to the pathways of interferon production (see Section 3-7). Plasmacytoid dendritic cells express a subset of TLRs that includes TLR-7 and TLR-9, which are endosomal sensors of viral RNA and of the nonmethylated CpG residues present in the genomes of many DNA viruses (see Fig. 3.11). The requirement for TLR-9 in sensing infections caused by DNA viruses has been demonstrated, for example, by the


Immunology_Janeway

Immunology_Janeway. nonmethylated CpG residues present in the genomes of many DNA viruses (see Fig. 3.11). The requirement for TLR-9 in sensing infections caused by DNA viruses has been demonstrated, for example, by the inability of TLR-9-deficient plasmacytoid dendritic cells to generate type I interferons in response to herpes simplex virus. Plasmacytoid dendritic cells express CXCR3, a receptor for the chemokines CXCL9, CXCL10, and CXCL11, which are produced by T cells. This allows pDCs to migrate from the blood into lymph nodes in which there is an ongoing inflammatory response to a pathogen.


Immunology_Janeway

Immunology_Janeway. Interferons help defend against viral infection in several ways (Fig. 3.35). IFN-β is particularly important because it induces cells to make IFN-α, thus amplifying the interferon response. Interferons act to induce a state of resistance to viral replication in all cells. IFN-α and IFN-β bind to a common cell-surface receptor, known as the interferon-α receptor (IFNAR), which uses the JAK and STAT pathways described in Section 3-16. IFNAR uses the kinases Tyk2 and Jak1 to activate the factors STAT1 and STAT2, which can interact with IRF9 and form a complex called ISGF3 that binds to the promoters of many interferon stimulated genes (ISGs).


Immunology_Janeway

Immunology_Janeway. One ISG encodes the enzyme oligoadenylate synthetase, which polymerizes ATP into 2ʹ–5ʹ-linked oligomers (whereas nucleotides in nucleic acids are normally linked 3ʹ–5ʹ). These 2ʹ–5ʹ-linked oligomers activate an endoribonuclease that then degrades viral RNA. A second protein induced by IFN-α and IFN-βis a dsRNA-dependent protein kinase called PKR. This serine–threonine kinase phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), thus suppressing protein translation and contributing to the inhibition of viral replication. Mx (myxoma resistant) proteins are also induced by type I interferons. Humans and wild mice have two highly similar proteins, Mx1 and Mx2, which are GTPases belonging to the dynamin protein family, but how they interfere with viral replication is not understood. Oddly, most common laboratory strains of mice have inactivated both Mx genes, and in these mice, IFN-β cannot act to protect against influenza infection.


Immunology_Janeway

Immunology_Janeway. In the last few years, several novel ISGs have been identified and linked to antiviral functions. The IFIT (IFN-induced protein with tetratricoid repeats) family contains four human and three mouse proteins that function in restraining the translation of viral RNA into proteins. IFIT1 and IFIT2 can both suppress the translation of normal capped mRNAs by binding to subunits of the eukaryotic initiation factor 3 (eIF3) complex, which prevents eIF3 from interacting with eIF2 to form the 43S pre-initiation complex (Fig. 3.36). This action may be responsible in part for the reduction in cellular proliferation induced by type I interferons. Mice lacking IFIT1 or IFIT2 show increased susceptibility to infection by certain viruses, such as vesicular stomatitis virus.


Immunology_Janeway

Immunology_Janeway. Another function of IFIT1 is to suppress translation of viral RNA that lacks a normal host modification of the 5ʹ cap. Recall that the normal mammalian 5ʹ cap is initiated by linking a 7-methylguanosine nucleotide to the first ribose sugar of the mRNA by a 5ʹ–5ʹ triphosphate bridge, to produce a structure called cap-0. This structure is further modified by cytoplasmic methylation of the 2ʹ hydroxyl groups on the first and second ribose sugars of the RNA. Methylation of the first ribose sugar produces a structure called cap-1; methylation of the second generates cap-2. IFIT1 has a high affinity for cap-0, but much lower affinity for cap-1 and cap-2. Some viruses, such as Sindbis virus (family Togaviridae), lack 2ʹ-O-methylation, and therefore are restricted by this action of IFIT1. Many viruses, such as West Nile virus and SARS coronavirus, have acquired a 2ʹe-O-methyltransferase (MTase) that produce cap-1 or cap-2 on their viral transcripts. These viruses can thus evade restriction by


Immunology_Janeway

Immunology_Janeway. such as West Nile virus and SARS coronavirus, have acquired a 2ʹe-O-methyltransferase (MTase) that produce cap-1 or cap-2 on their viral transcripts. These viruses can thus evade restriction by IFIT1.


Immunology_Janeway

Immunology_Janeway. Members of the interferon-induced transmembrane protein (IFITM) family are expressed at a basal level on many types of tissues but are strongly induced by type I interferons. There are four functional IFITM genes in humans and in mice, and these encode proteins that have two transmembrane domains and are localized to various vesicular compartments of the cell. IFITM proteins act to inhibit, or restrict, viruses at early steps of infection. Although the molecular details are unclear, IFITM1 appears to interfere with the fusion of viral membranes with the membrane of the lysosome, which is required for introducing some viral genomes into the cytoplasm. Viruses that must undergo this fusion event in lysosomes, such as the Ebola virus, are restricted by IFITM1. Similarly, IFITM3 interferes with membrane fusion in late endosomes, and so restricts the influenza A virus, which undergoes fusion there. The importance of this mechanism is demonstrated by the increased viral load and higher


Immunology_Janeway

Immunology_Janeway. with membrane fusion in late endosomes, and so restricts the influenza A virus, which undergoes fusion there. The importance of this mechanism is demonstrated by the increased viral load and higher mortality in mice lacking IFITM3 that are infected with the influenza A virus.


Immunology_Janeway

Immunology_Janeway. Interferons also stimulate production of the chemokines CXCL9, CXCL10, and CXCL11, which recruit lymphocytes to sites of infection. They also increase the expression of MHC class I molecules on all types of cells, which facilitates recognition of virally infected cells by cytotoxic T lymphocytes via the display of viral peptides complexed to MHC class I molecules on the infected cell surface (see Fig. 1.30). Through these effects, interferons indirectly help promote the killing of virus-infected cells by CD8 cytotoxic T cells. Another way in which interferons act is to activate populations of innate immune cells, such as NK cells, that can kill virus-infected cells, as described below. 3-23 Several types of innate lymphoid cells provide protection in early infection.


Immunology_Janeway

Immunology_Janeway. A defining feature of adaptive immunity is the clonal expression of antigen receptors, produced by somatic gene rearrangements, that provide the extraordinarily diverse specificities of T and B lymphocytes (see Section 1-11). However, for several decades, immunologists have recognized cells that have lymphoid characteristics but which lack specific antigen receptors. Natural killer (NK) cells have been known the longest, but in the past several years other distinct groups of such cells have been identified. Collectively, these are now called innate lymphoid cells (ILCs) and include NK cells (Fig. 3.37). ILCs develop in the bone marrow from the same common lymphocyte progenitor (CLP) that gives rise to B and T cells. Expression of the transcription factor Id2 (inhibitor of DNA binding 2) in the CLP represses Band T-cell fates, and is required for the development of all ILCs. ILCs are identified by the absence of Tand B-cell antigen receptor and co-receptor complexes, but they express


Immunology_Janeway

Immunology_Janeway. in the CLP represses Band T-cell fates, and is required for the development of all ILCs. ILCs are identified by the absence of Tand B-cell antigen receptor and co-receptor complexes, but they express the receptor for IL-7. They migrate from the bone marrow and populate lymphoid tissues and peripheral organs, notably the dermis, liver, small intestine, and lung.


Immunology_Janeway

Immunology_Janeway. ILCs function in innate immunity as effector cells that amplify the signals delivered by innate recognition. They are stimulated by cytokines produced by other innate cells, such as macrophages or dendritic cells, that have been activated by innate sensors of microbial infection or cellular damage. Three major subgroups of ILCs are defined, largely on the basis of the types of cytokines that each produces. Group 1 ILCs (ILC1s) generate IFN-γ in response to activation by certain cytokines, in particular IL-12 and IL-18, made by dendritic cells and macrophages, and they function in protection against infection by viruses or intracellular pathogens. NK cells are now considered to be a type of ILC. ILC1s and NK cells are closely related, but have distinct functional properties and differ in the factors required for their development. NK cells are more similar to CD8 T cells in function, while ILC1s resemble more closely the TH1 subset of CD4 T cells (see Section 3-24). NK cells can be


Immunology_Janeway

Immunology_Janeway. the factors required for their development. NK cells are more similar to CD8 T cells in function, while ILC1s resemble more closely the TH1 subset of CD4 T cells (see Section 3-24). NK cells can be distinguished from recently identified ILC1 cells in several ways. NK cells can be found within tissues, but they also circulate through the blood, while ILC1 cells appear to be largely non-circulating tissue-resident cells. In the mouse, conventional NK cells express the integrin α2 (CD49b), while ILC1 cells, for example in the liver, lack CD49b but express the surface protein Ly49a. Both NK and ILC1 cells require the transcription factor Id2 for their development, but NK cells require the cytokine IL-15 and the transcription factors Nfil3 and eomesodermin, while liver ILC1 cells require the cytokine IL-7 and the transcription factor Tbet.


Immunology_Janeway

Immunology_Janeway. ILC2s produce the cytokines IL-4, IL-5, and IL-13, in response to various cytokines, particularly thymic stromal lymphopoietin (TSLP) and IL-33. ILC2 cytokines function in promoting mucosal and barrier immunity and aid in protection against parasites. ILC3s respond to the cytokines IL-1β and IL-23 and produce several cytokines, including IL-17 and IL-22, which increase defenses against extracellular bacteria and fungi. IL-17 functions by stimulating the production of chemokines that recruit neutrophils, while IL-22 acts directly on epithelial cells to stimulate the production of antimicrobial peptides such as RegIIIγ (see Section 2-4).


Immunology_Janeway

Immunology_Janeway. The classification of ILC subtypes and the analysis of their development and function is still an active area, and studies to define the relative importance of these cells in immune responses are ongoing. The ILC subgroups identified so far appear to be highly parallel in structure to the subsets of effector CD8 and CD4 T cells that were defined over the last three decades. The transcription factors that control the development of different ILC subsets seem, for now at least, to be the same as those that control the corresponding T-cell subsets. Because of these similarities, we will postpone a detailed description of ILC development until Chapter 9, where we will cover this topic along with the development of T-cell subsets. 3-24 NK cells are activated by type I interferon and macrophage-derived cytokines.


Immunology_Janeway

Immunology_Janeway. NK cells are larger than T and B cells, have distinctive cytoplasmic granules containing cytotoxic proteins, and are functionally identified by their ability to kill certain tumor cell lines in vitro without the need for specific immunization. NK cells kill cells by releasing their cytotoxic granules, which are similar to those of cytotoxic T cells and have the same effects (discussed in Chapter 9). In brief, the contents of cytotoxic granules, which contain granzymes and the pore-forming protein perforin, are released onto the surface of the target cell, and penetrate the cell membrane and induce programmed cell death. However, unlike T cells, killing by NK cells is triggered by germline-encoded receptors that recognize molecules on the surface of infected or malignantly transformed cells. A second pathway used by NK cells to kill target cells involves the TNF family member known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). NK cells express TRAIL on their cell


Immunology_Janeway

Immunology_Janeway. A second pathway used by NK cells to kill target cells involves the TNF family member known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). NK cells express TRAIL on their cell surface. TRAIL interacts with two TNFR superfamily ‘death’ receptors, DR4 and DR5 (encoded by TNFSF10A and B), that are expressed by many types of cells. When NK cells recognize a target cell, TRAIL stimulates DR4 and DR5 to activate the pro-enzyme caspase 8, which leads to apoptosis. In contrast to pyroptosis, induced by caspase 1 following inflammasome activation (see Section 3-9), apoptosis is not associated with production of inflammatory cytokines. We will return to discuss more details of the mechanisms of caspase-induced apoptosis when we discuss killing by cytotoxic T cells in Chapter 9. Finally, NK cells express Fc receptors (see Section 1-20); binding of antibodies to these receptors activates NK cells to release their cytotoxic granules, a process known as antibody-dependent


Immunology_Janeway

Immunology_Janeway. 9. Finally, NK cells express Fc receptors (see Section 1-20); binding of antibodies to these receptors activates NK cells to release their cytotoxic granules, a process known as antibody-dependent cellular cytotoxicity, or ADCC, to which we will return in Chapter 10.


Immunology_Janeway

Immunology_Janeway. The ability of NK cells to kill target cells can be enhanced by interferons or certain cytokines. NK cells that can kill sensitive targets can be isolated from uninfected individuals, but this activity is increased 20to 100-fold when NK cells are exposed to IFN-αand IFN-β, or to IL-12, a cytokine produced by dendritic cells and macrophages during infection by many types of pathogens. Activated 1 2 3 4 5 6 7 8 9 10 time after viral infection (days) NK-cell-mediated killing of infected cells T-cell-mediated killing of infected cells virus titer production of IFN-˜, IFN-°, TNF-˜, and IL-12


Immunology_Janeway

Immunology_Janeway. Fig. 3.38 Natural killer cells (NK cells) are an early component of the host response to virus infection. Experiments in mice have shown that IFN-α, IFN-β, and the cytokines TNF-α and IL-12 are produced first, followed by a wave of NK cells, which together control virus replication but do not eliminate the virus. Virus elimination is accomplished when virus-specific CD8 T cells and neutralizing antibodies are produced. Without NK cells, the levels of some viruses are much higher in the early days of the infection, and the infection can be lethal unless treated vigorously with antiviral compounds.


Immunology_Janeway

Immunology_Janeway. NK cells serve to contain virus infections while the adaptive immune response is generating antigen-specific cytotoxic T cells and neutralizing antibodies that can clear the infection (Fig. 3.38). A clue to the physiological function of NK cells in humans comes from rare patients deficient in these cells, who are frequently susceptible to herpesvirus infection. For example, a selective NK-cell deficiency results from mutations in the human MCM4 (minichromosome maintenance-deficient 4) protein, which is associated with predisposition to viral infections.


Immunology_Janeway

Immunology_Janeway. IL-12, acting in synergy with the cytokine IL-18 produced by activated macrophages, can also stimulate NK cells to secrete large amounts of interferon (IFN)-γ, and this is crucial in controlling some infections before the IFN-γ produced by activated CD8 cytotoxic T cells becomes available. IFN-γ, whose receptor activates only the STAT1 transcription factor, is quite distinct functionally from the antiviral type I interferons IFN-α and IFN-β, and is not directly induced by viral infection. The production of IFN-γ by NK cells early in an immune response can directly activate macrophages to enhance their capacity to kill pathogens, augmenting innate immunity, but also influences adaptive immunity through actions on dendritic cells and in regulating the differentiation of CD4 T cells into the pro-inflammatory TH1 subset, which produces IFN-γ. NK cells also produce TNF-α, granulocyte-macrophage stimulating factor (GM-CSF), and the chemokines CCL3 (MIF 1-α), CCL4, and CCL5 (RANTES), which


Immunology_Janeway

Immunology_Janeway. pro-inflammatory TH1 subset, which produces IFN-γ. NK cells also produce TNF-α, granulocyte-macrophage stimulating factor (GM-CSF), and the chemokines CCL3 (MIF 1-α), CCL4, and CCL5 (RANTES), which act to recruit and activate macrophages.


Immunology_Janeway

Immunology_Janeway. 3-25 NK cells express activating and inhibitory receptors to distinguish between healthy and infected cells.


Immunology_Janeway

Immunology_Janeway. For NK cells to defend against viruses or other pathogens, they should be able to distinguish infected cells from uninfected healthy cells. However, the mechanism used by NK cells is slightly more complicated than pathogen recognition by T or B cells. In general, it is thought that an individual NK cell expresses various combinations of germline-encoded activating receptors and inhibitory receptors. While the exact details are not clear in every case, it is thought that the overall balance of signaling by these receptors determines whether an NK cell engages and kills a target cell. The receptors on an NK cell are tuned to detect changes in expression of various surface proteins on a target cell, referred to as ‘dysregulated self.’ The activating receptors generally recognize cell-surface proteins that are induced on target cells by metabolic stress, such as malignant transformation or microbial infection. These changes are referred to as ‘stress-induced self.’ Specific cellular


Immunology_Janeway

Immunology_Janeway. proteins that are induced on target cells by metabolic stress, such as malignant transformation or microbial infection. These changes are referred to as ‘stress-induced self.’ Specific cellular events, including DNA damage, signals related to proliferation, heat-shock related stress, and signaling by innate sensors including TLRs can lead to expression by host cells of surface proteins that bind to the activating receptors on NK cells. Stimulation of activating receptors will add to the chance that the NK cells will release cytokines such as IFN-γ and activate the killing of the stimulating cell through the release of cytotoxic granules.


Immunology_Janeway

Immunology_Janeway. By contrast, inhibitory receptors on NK cells recognize surface molecules that are constitutively expressed at high levels by most cells, and the loss of these molecules is referred to as ‘missing self.’ Inhibitory receptors can recognize other molecules, but those recognizing MHC class I molecules have been studied the most so far. MHC molecules are glycoproteins expressed on nearly all cells of the body. We will discuss the role of MHC proteins in antigen presentation to T cells in Chapter 6, but for now we need only to introduce the two main classes of MHC molecules. MHC class I molecules are expressed on most of the cells of the body (except, notably, red blood cells), whereas the expression of MHC class II molecules is far more restricted, largely to immune cells.


Immunology_Janeway

Immunology_Janeway. Inhibitory receptors that recognize MHC class I molecules function to prevent NK cells from killing normal host cells. The greater the number of MHC class I molecules on a cell surface, the better protected that cell is against attack by NK cells. Interferons induce expression of MHC class I molecules, and protect uninfected host cells from being killed by NK cells, while also activating NK cells to kill virus-infected cells. Viruses and some other intracellular pathogens can cause downregulation of MHC class I molecules as a strategy to prevent the display of antigens as peptides to T cells, also discussed in Chapter 6. NK cells are able to sense this reduction in expression of MHC class I molecules through reduced signaling from their inhibitory receptors. Reduction in MHC class I expression is an example of ‘missing self,’ and increases the chance that an NK cell will kill the target cell. It is thought that the balance of signals from ‘stress-induced self’ and ‘missing self’


Immunology_Janeway

Immunology_Janeway. expression is an example of ‘missing self,’ and increases the chance that an NK cell will kill the target cell. It is thought that the balance of signals from ‘stress-induced self’ and ‘missing self’ determines whether an individual NK cell will be triggered to kill a particular target cell (Fig. 3.39). Thus receptors expressed on NK cells integrate the signals from two types of


Immunology_Janeway

Immunology_Janeway. Fig. 3.39 Killing by NK cells depends on the balance between activating and inhibitory signals. NK cells have several different activating receptors that signal the NK to kill the bound cell. However, NK cells are prevented from a wholesale attack by another set of inhibitory receptors that recognize MHC class I molecules (which are present on almost all cell types) and that inhibit killing by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I, such as in cells infected with viruses, many of which specifically inhibit MHC class I expression or alter its conformation so as to avoid recognition by CD8 T cells. NK cells may also kill target cells through their expression of the TNF family member TRAIL, which binds to TNFR members DR4 and DR5 expressed by some types of cells. DR4 and DR5 signal through FADD, an adaptor that activates pro-caspase 8, leading to induction of apoptosis of the target cell.


Immunology_Janeway

Immunology_Janeway. Fig. 3.40 The genes that encode NK receptors fall into two large families.


Immunology_Janeway

Immunology_Janeway. The first, the leukocyte receptor complex (LRC), comprises a large cluster of genes encoding a family of proteins composed of immunoglobulin-like domains. These include the killer cell immunoglobulin-like receptors (KIRs) expressed by NK cells, the ILT (immunoglobulin-like transcript) class, and the leukocyte-associated immunoglobulin-like receptor (LAIR) gene families. The sialic acid-binding Ig-like lectins (SIGLECs) and members of the CD66 family are located nearby. In humans, this complex is located on chromosome 19. The second gene cluster is called the NK receptor complex (NKC) and encodes killer cell lectin-like receptors (KLRs), a receptor family that includes the NKG2 proteins and CD94, with which some NKG2 molecules pair to form a functional receptor. This complex is located on human chromosome 12. Some NK receptor genes are found outside these two major gene clusters; for example, the genes for the natural cytotoxicity receptors NKp30 and NKp44 are located within the major


Immunology_Janeway

Immunology_Janeway. human chromosome 12. Some NK receptor genes are found outside these two major gene clusters; for example, the genes for the natural cytotoxicity receptors NKp30 and NKp44 are located within the major histocompatibility complex on chromosome 6. Figure based on data courtesy of J. Trowsdale University of Cambridge.


Immunology_Janeway

Immunology_Janeway. surface receptors, which together control the NK cell’s cytotoxic activity and cytokine production. 3-26 NK-cell receptors belong to several structural families, the KIRs, KLRs, and NCRs.


Immunology_Janeway

Immunology_Janeway. The receptors that regulate the activity of NK cells fall into two large families that contain a number of other cell-surface receptors in addition to NK receptors (Fig. 3.40). Members of the killer cell immunoglobulin-like receptor family, or KIRs, have differing numbers of immunoglobulin domains. Some, such as KIR-2D, have two immunoglobulin domains, whereas others, such as KIR-3D, have three. The KIR genes form part of a larger cluster of immunoglobulin-like receptor genes known as the leukocyte receptor complex (LRC). Another family, the killer cell lectin-like receptors, or KLRs, are C-type lectin-like proteins whose genes reside within a gene cluster called the NK receptor complex (NKC). Mice lack KIR genes, and instead predominantly express Ly49 receptors encoded in the NKC on mouse chromosome 6 to control their NK-cell activity. These receptors can be activating or inhibitory, and are highly polymorphic between different strains of mice. By contrast, humans lack functional


Immunology_Janeway

Immunology_Janeway. chromosome 6 to control their NK-cell activity. These receptors can be activating or inhibitory, and are highly polymorphic between different strains of mice. By contrast, humans lack functional Ly49 genes and rely on KIRs encoded in the LRC to control their NK-cell activity. An important feature of the NK-cell population is that any given NK cell expresses only a subset of the receptors in its potential repertoire, and so not all NK cells in the individual are identical.


Immunology_Janeway

Immunology_Janeway. Activating and inhibitory receptors are present within the same structural family. Whether a KIR protein is activating or inhibitory depends on the presence or absence of particular signaling motifs in its cytoplasmic domain. Inhibitory KIRs have long cytoplasmic tails that contain an immunoreceptor tyrosine-based inhibition motif (ITIM). The consensus sequence for the ITIM is V/I/LxYxxL/V, where x stands for any amino acid. For example, the cytoplasmic tails of the inhibitory receptors KIR-2DL and KIR-3DL each contain two ITIMs (Fig. 3.41). When ligands associate with an inhibitory KIR, the tyrosine in its ITIM becomes phosphorylated by the action of Src family protein tyrosine kinases. When phosphorylated, the ITIM can then bind the intracellular protein tyrosine phosphatases SHP-1 (src homology region 2-containing protein tyrosine phosphatase-1) and SHP-2, which become localized near the cell membrane. These phosphatases inhibit signaling induced by other receptors by removing


Immunology_Janeway

Immunology_Janeway. (src homology region 2-containing protein tyrosine phosphatase-1) and SHP-2, which become localized near the cell membrane. These phosphatases inhibit signaling induced by other receptors by removing phosphates from tyrosine residues on other intracellular signaling molecules.


Immunology_Janeway

Immunology_Janeway. Activating KIRs have short cytoplasmic tails, designated, for example, as KIR2DS and KIR-3DS (see Fig. 3.41). These receptors lack an ITIM and instead have a charged residue in their transmembrane regions that associates with an accessory signaling protein called DAP12. DAP12 is a transmembrane protein that contains an immunoreceptor tyrosine-based activation motif (ITAM, with consensus sequence YXX[L/I]X6–9YXX[L/I]) in its cytoplasmic tail and forms a disulfide-linked homodimer in the membrane. When a ligand binds to an activating KIR, the tyrosine residues in the ITAM of DAP12 become phosphorylated, turning on intracellular signaling pathways that activate the NK cell and lead to release of the cytotoxic granules. The phosphorylated ITAMs bind and activate intracellular tyrosine kinases such as Syk or ZAP-70, leading to further signaling events similar to those described for T cells in Chapter 7.


Immunology_Janeway

Immunology_Janeway. The KLR family also has both activating and inhibitory members. In mice, inhibitory Ly49 receptors have an ITIM in their cytoplasmic tail that recruits SHP-1. The latter’s importance is shown by the failure of Ly49 to inhibit NK activation upon binding to MHC class I in mice carrying the motheaten mutation, which inactivates SHP-1 protein. In humans and mice, NK cells express a heterodimer of two different C-type lectin-like receptors, CD94 and NKG2. This heterodimer interacts with nonpolymorphic MHC class I-like molecules, including HLA-E in humans and Qa1 in mice. HLA-E and Qa1 are unusual in that instead of binding peptides derived from pathogens, they bind fragments of the signal peptide derived from other MHC class I molecules during processing in the endoplasmic reticulum. This enables CD94:NKG2 to detect the presence of several different MHC class I variants, whose expression may be targeted by viruses, and kill cells in which overall MHC molecule expression is diminished. In


Immunology_Janeway

Immunology_Janeway. CD94:NKG2 to detect the presence of several different MHC class I variants, whose expression may be targeted by viruses, and kill cells in which overall MHC molecule expression is diminished. In humans there are four closely related NKG2 family proteins, NKG2A, C, E, and F (encoded by KLRC1–4), and a more distantly related protein, NKG2D (encoded by KLRK1). Of these, for example, NKG2A contains an ITIM and is inhibitory, whereas NKG2C has a charged transmembrane residue, associates with DAP12, and is activating (see Fig. 3.41). NKG2D is also activating but quite distinct from the other NKG2 receptors, and we will discuss it separately below.


Immunology_Janeway

Immunology_Janeway. The overall response of NK cells to differences in MHC expression is further complicated by the extensive polymorphism of KIR genes, with different numbers of activating and inhibitory KIR genes being found in different people. This may explain why NK cells are a barrier to bone marrow transplantation, since the NK cells of the recipient may react more strongly to donor MHC molecules than to the self MHC with which they developed. A similar phenomenon may occur during pregnancy, because of differences between fetal and maternal MHC molecules (see Section 15-38). The advantage of such extensive KIR polymorphism is not yet clear, and some genetic epidemiologic studies even suggest an association between certain alleles of KIR genes and earlier onset (although not absolute frequency) of rheumatoid arthritis. The KIR gene cluster is not present in mice, but some species, including some primates, contain genes of both the KIR and KLR families. This might suggest that both gene clusters are


Immunology_Janeway

Immunology_Janeway. arthritis. The KIR gene cluster is not present in mice, but some species, including some primates, contain genes of both the KIR and KLR families. This might suggest that both gene clusters are relatively ancient and that for some reason, one or the other gene cluster was lost by mice and humans.


Immunology_Janeway

Immunology_Janeway. Signaling by the inhibitory NK receptors suppresses the killing activity and cytokine production of NK cells. This means that NK cells will not kill healthy, genetically identical cells with normal expression of MHC class I molecules, such as the other cells of the body. Virus-infected cells, however, can become susceptible to being killed by NK cells by a variety of mechanisms. First, some viruses inhibit all protein synthesis in their host cells, so that synthesis of MHC class I proteins would be blocked in infected cells, even while their production in uninfected cells is being stimulated by the actions of type I interferons. The reduced level of MHC class I expression in infected cells would make them correspondingly less able to inhibit NK cells through their MHC-specific receptors, and they would become more susceptible to being killed. Second, many viruses can selectively prevent the export of MHC class I molecules to the cell surface, or induce their degradation once there.


Immunology_Janeway

Immunology_Janeway. and they would become more susceptible to being killed. Second, many viruses can selectively prevent the export of MHC class I molecules to the cell surface, or induce their degradation once there. This might allow the infected cell to evade recognition by cytotoxic T cells but would make it


Immunology_Janeway

Immunology_Janeway. Fig. 3.41 The structural families of NK receptors encode both activating and inhibitory receptors. The families of killer cell immunoglobulin-like receptors (KIRs) and killer cell lectin-like receptors (KLRs) have members that send activating signals to the NK cell (upper panel) and those that send inhibitory signals (lower panel). KIR family members are designated according to the number of immunoglobulin-like domains they possess and by the length of their cytoplasmic tails. Activating KIR receptors have short cytoplasmic tails and bear the designation ‘S.’ These associate with the signaling protein DAP12 via a charged amino acid residue in the transmembrane region. The cytoplasmic tails of DAP12 contain amino acid motifs called ITAMs, which are involved in signaling. NKG2 receptors belong to the KLR family, and, whether activating or inhibitory, form heterodimers with another C-type lectin-like family member, CD94. The inhibitory KIR receptors have longer cytoplasmic tails and are


Immunology_Janeway

Immunology_Janeway. to the KLR family, and, whether activating or inhibitory, form heterodimers with another C-type lectin-like family member, CD94. The inhibitory KIR receptors have longer cytoplasmic tails and are designated ‘L’; these do not associate constitutively with adaptor proteins but contain a signaling motif called an ITIM, which when phosphorylated is recognized by inhibitory phosphatases.


Immunology_Janeway

Immunology_Janeway. Fig. 3.42 Activating receptors of NK cells include the natural cytotoxicity receptors and NKG2D. The natural cytotoxicity receptors are immunoglobulinlike proteins. NKp30 and NKp44, for example, have an extracellular domain that resembles a single variable domain of an immunoglobulin molecule. NKp30 and NKp46 activate the NK cell through their association with homodimers of the CD3ζ chain, or the Fc receptor γ chain (not shown). These signaling proteins also associate with other types of receptors that are described in Chapter 7. NKp44 activates the NK cell through their association with homodimers of DAP12. NKp46 resembles the KIR-2D molecules in having two domains that resemble the constant domains of an immunoglobulin molecule. NKG2D is a member of the C-type lectin-like family and forms a homodimer, and it associates with DAP10. In mice, an alternatively spliced form of NKG2D also associates with DAP12 (not shown).


Immunology_Janeway

Immunology_Janeway. The ligands for NKG2D are MHC-like molecules, MIC-A, MIC-B, or RAET1 family members, whose expression is induced by cellular stress MIC-A or MIC-B RAET1 family (includes MULT1, ULBPs) susceptible to being killed by NK cells. Virally infected cells can still be killed by NK cells even if the cells do not downregulate MHC, provided that ligands for activating receptors are induced. However, some viruses target ligands for the activating receptors on NK cells, thwarting NK-cell recognition and killing of virus-infected cells 3-27 NK cells express activating receptors that recognize ligands induced on infected cells or tumor cells.


Immunology_Janeway

Immunology_Janeway. In addition to the KIRs and KLRs, which have a role in sensing the level of MHC class I proteins present on other cells, NK cells also express receptors that more directly sense the presence of infection or other perturbations in a cell. Activating receptors for the recognition of infected cells, tumor cells, and cells injured by physical or chemical damage include the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46, which are immunoglobulin-like receptors, and the C-type lectin-like family members Ly49H and NKG2D (Fig. 3.42). Among NCRs, only NKp46 is conserved in humans and in mice, and it is the most selective marker of NK cells across mammalian species. The ligands recognized by the NCRs are still being defined, but some evidence suggests that they recognize viral proteins, including the hemagglutinin (HA) glycoprotein of the influenza virus. Ly49H is an activating receptor that recognizes the viral protein m157, an MHC class I-like structure encoded by the murine


Immunology_Janeway

Immunology_Janeway. including the hemagglutinin (HA) glycoprotein of the influenza virus. Ly49H is an activating receptor that recognizes the viral protein m157, an MHC class I-like structure encoded by the murine cytomegalovirus. The ligand for NKp30 is a protein named B7-H6, a member of the family of co-stimulatory proteins mentioned in Section 1-15, and is further described in Chapters 7 and 9.


Immunology_Janeway

Immunology_Janeway. NKG2D has a specialized role in activating NK cells. NKG2 family members form heterodimers with CD94 and bind the MHC class I molecule HLA-E. In contrast, two NKG2D molecules form a homodimer that binds to several MHC class I-like molecules that are induced by various types of cellular stress. These include the MIC molecules MIC-A and MIC-B, and the RAET1 family of proteins, which are similar to the α1 and α2 domains of MHC class I molecules (Fig. 3.43). The RAET1 family has 10 members, 3 of which were initially characterized as ligands for the cytomegalovirus UL16 protein and are also called UL16-binding proteins, or ULBPs. Mice do not have equivalents of the MIC molecules; the ligands for mouse NKG2D have a very similar structure to that of the RAET1 proteins, and are probably orthologs of them. In fact, these ligands were first identified in mice as the RAE1 (retinoic acid early inducible 1) protein family, and also include related proteins H60 and MULT1 (see Fig. 6.26). We will


Immunology_Janeway

Immunology_Janeway. of them. In fact, these ligands were first identified in mice as the RAE1 (retinoic acid early inducible 1) protein family, and also include related proteins H60 and MULT1 (see Fig. 6.26). We will return to these MHC-like molecules when we discuss the structure of the MHC molecule in Section 6-18.


Immunology_Janeway

Immunology_Janeway. The ligands for NKG2D are expressed in response to cellular or metabolic stress, and so are upregulated on cells infected with intracellular bacteria and most viruses, as well as on incipient tumor cells that have become malignantly transformed. Thus, recognition by NKG2D acts as a generalized ‘danger’ signal to the immune system. In addition to expression by a subset of NK cells, NKG2D is expressed by various T cells, including all human CD8 T cells, γ:δ T cells, activated murine CD8 T cells, and invariant NKT cells (described in Chapter 8). In these cells, recognition of NKG2D ligands provides a potent co-stimulatory signal that enhances their effector functions.


Immunology_Janeway

Immunology_Janeway. Fig. 3.43 The ligands for the activating NK receptor NKG2D are proteins that are expressed in conditions of cellular stress. The MIC proteins MIC-A and MIC-B are MHC-like molecules induced on epithelial and other cells by stress, such as DNA damage, cellular transformation, or infection. RAET1 family members, including the subset designated as UL16-binding proteins (ULBPs), also resemble a portion of an MHC class I molecule—the α1 and α2 domains—and most (but not all) are attached to the cell via a glycophosphatidylinositol linkage. Unlike MHC class I molecules, the NKG2D ligands do not bind processed peptides.


Immunology_Janeway

Immunology_Janeway. NKG2D also differs from other activating receptors on NK cells in the signaling pathway it engages within the cell. The other activating receptors are associated intracellularly with signaling proteins such as the CD3ζ chain, the Fc receptor γ chain, and DAP12, which all contain ITAMs. In contrast, NKG2D binds a different adaptor protein, DAP10, which does not contain an ITAM sequence and instead activates the intracellular lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase), initiating a different series of intracellular signaling events in the NK cell (see Section 7-4). Generally, PI 3-kinase is considered to enhance the survival of cells in which it is activated, thereby augmenting the cell’s overall effector activity. In NK cells, activation of PI 3-kinase is directly linked to the induction of cytotoxic activity. In mice, the workings of NKG2D are even more complicated, because mouse NKG2D is produced in two alternatively spliced forms, one of which binds DAP12 and DAP10,


Immunology_Janeway

Immunology_Janeway. the induction of cytotoxic activity. In mice, the workings of NKG2D are even more complicated, because mouse NKG2D is produced in two alternatively spliced forms, one of which binds DAP12 and DAP10, whereas the other binds only DAP10. Mouse NKG2D can thus activate both signaling pathways, whereas human NKG2D seems to signal only through DAP10 to activate the PI 3-kinase pathway. Finally, NK cells express several receptors from the SLAM (signaling lymphocyte activation molecule) family, including 2B4, which recognizes the cell-surface molecule CD48 expressed by many cells including NK cells. Interactions between 2B4 and CD48 on nearby NK cells can release signals that promote survival and proliferation through SAP (SLAM-associated protein) and the Src kinase Fyn.


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Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Triggering of innate sensors on various cells—neutrophils, macrophages, and dendritic cells in particular—not only activates these cells’ individual effector functions, but also stimulates the release of pro-inflammatory chemokines and cytokines that act together to recruit more phagocytic cells to the site of infection. Especially prominent is the early recruitment of neutrophils and monocytes. Furthermore, cytokines released by tissue phagocytic cells can induce more systemic effects, including fever and the production of acute-phase response proteins, including mannose-binding lectin, C-reactive protein, fibrinogen, and pulmonary surfactant proteins, which add to a general state of augmented innate immunity. These cytokines also mobilize antigen-presenting cells that induce the adaptive immune response. The innate immune system has at its service several recently recognized subtypes of innate lymphoid cells which join the ranks of the long-recognized NK cells. ILCs exhibit


Immunology_Janeway

Immunology_Janeway. adaptive immune response. The innate immune system has at its service several recently recognized subtypes of innate lymphoid cells which join the ranks of the long-recognized NK cells. ILCs exhibit specialized effector activity in response to different signals, and act to amplify the strength of the innate response. The production of interferons in response to viral infections serves to inhibit viral replication and to activate NK cells. These in turn can distinguish healthy cells from those that are infected by virus or that are transformed or stressed in some way, based on the expression of class I MHC molecules and MHC-related molecules that are ligands for some NK receptors. As we will see later in the book, cytokines, chemokines, phagocytic cells, and NK cells are all effector mechanisms that are also employed in the adaptive immune response, which uses variable receptors to target specific pathogen antigens.


Immunology_Janeway

Summary to Chapter 3.

Immunology_Janeway. Summary to Chapter 3.


Immunology_Janeway

Immunology_Janeway. Innate immunity uses a variety of effector mechanisms to detect infection and eliminate pathogens, or hold them in check until an adaptive immune response develops. These effector mechanisms are all regulated by germline-encoded receptors on many types of cells that can detect molecules of microbial origin or that sense signs of host cellular damage. The induced responses of the innate immune system are based on several distinct components. After the initial barriers—the body’s epithelia and the soluble antimicrobial molecules described in Chapter 2—have been breached, the most important innate defenses rely on tissue macrophages and other tissue-resident sensor cells, such as dendritic cells. Macrophages provide a double service: they mediate rapid cellular defense at the borders of infection through phagocytosis and antimicrobial actions, and they also use their various innate sensors to activate the process of inflammation, which involves recruiting additional cells to sites of


Immunology_Janeway

Immunology_Janeway. through phagocytosis and antimicrobial actions, and they also use their various innate sensors to activate the process of inflammation, which involves recruiting additional cells to sites of infection. Innate sensors activate signaling pathways that lead to the production of pro-inflammatory and antiviral cytokines, which in turn stimulate innate effector responses while also helping to initiate an adaptive immune response. The uncovering of the pathogen-sensing mechanisms described in this chapter is still extremely active. It is providing new insights into human autoinflammatory conditions such as lupus, Crohn’s disease, and gout. Indeed, the induction of powerful effector mechanisms by innate immune recognition based on germline-encoded receptors clearly has some dangers. It is a double-edged sword, as is illustrated by the effects of the cytokine TNF-α—beneficial when released locally, but disastrous when produced systemically. This illustrates the evolutionary knife edge along


Immunology_Janeway

Immunology_Janeway. sword, as is illustrated by the effects of the cytokine TNF-α—beneficial when released locally, but disastrous when produced systemically. This illustrates the evolutionary knife edge along which all innate mechanisms of host defense travel. The innate immune system can be viewed as a defense system that mainly frustrates the establishment of a focus of infection; however, even when it proves inadequate in fulfilling this function, it has already set in motion—by recruiting and activating dendritic cells—the initiation of the adaptive immune response, which forms an essential part of humans’ defenses against infection.


Immunology_Janeway

Immunology_Janeway. Having introduced immunology with a consideration of innate immune function, we next turn our attention to the adaptive immune response, beginning with an explanation of the structure and function of the antigen receptors expressed by lymphocytes. Questions. 3.1 Matching: Match the Toll-like receptor (TLR) to its ligand: A. TLR-2:TLR-1 or i. ssRNA TLR-2:TLR-6 B. TLR-3 ii. Lipopolysaccharide C. TLR-4 iii. Lipoteichoic acid and di-/triacyl lipoproteins D. TLR-5 iv. dsRNA E. TLR-7 v. Flagellin F. TLR-9 vi. Unmethylated CpG DNA 3.2 Matching: Match the hereditary disorder to the gene affected: A. Chronic granulomatous i. NOD2 disease B. X-linked hypohidrotic ii. IKKγ (NEMO) ectodermal dysplasia and immunodeficiency C. Crohn’s disease iii. Jak3 D. X-linked SCID iv. NAPDH oxidase E. SCID (not X-linked) v. NLRP3 F. Familial cold vi. γc inflammatory syndrome 3.3 Multiple Choice: Which of the following does not occur during an inflammatory response? A. Local blood clotting


Immunology_Janeway

Immunology_Janeway. E. SCID (not X-linked) v. NLRP3 F. Familial cold vi. γc inflammatory syndrome 3.3 Multiple Choice: Which of the following does not occur during an inflammatory response? A. Local blood clotting B. Tissue injury repair C. Endothelial cell activation D. Decreased vascular permeability E. Extravasation of leukocytes into inflamed tissue 3.4 Short Answer: What is the difference between conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs)? 3.5 Multiple Choice: Which of the following is a G-proteincoupled receptor? A. fMLF receptor B. TLR-4 C. IL-1R D. CD14 E. STING F. B7.1 (CD80) 3.6 True or False: All forms of ubiquitination lead to proteasomal degradation. 3.7 Fill-in-the-Blanks: A. Toll-like receptors (TLRs) have a cytoplasmic signaling domain called TIR that is also shared with __________.


Immunology_Janeway

Immunology_Janeway. 3.7 Fill-in-the-Blanks: A. Toll-like receptors (TLRs) have a cytoplasmic signaling domain called TIR that is also shared with __________. B. Cytokine receptors of the hematopoietin family activate tyrosine kinases of the _____ family, in order to signal these recruit SH2-domain-containing transcriptions factors called __________. C. Out of all the different TLRs, the only one that uses both MyD88/MAL and TRIF/TRAM adaptor pairs is __________. 3.8 True or False: Cytosolic DNA is sensed by cGAS, which signals through STING, while cytosolic ssRNA and dsRNA are sensed by RIG-I and MDA-5, respectively, which interact with the downstream adaptor protein MAVS. 3.9 Multiple Choice: Which of the following is not true? A. CCL2 attracts macrophages through CCR2. B. IL-3, IL-5, and GM-CSF are a subgroup of class I cytokine receptors that share a common β chain. C. IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 share a common γc.


Immunology_Janeway

Immunology_Janeway. B. IL-3, IL-5, and GM-CSF are a subgroup of class I cytokine receptors that share a common β chain. C. IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 share a common γc. D. The inflammasome is a large oligomer composed of the sensor NLRP3, the adaptor ASC, and caspase 8. E. CXCL8 attracts neutrophils through CXCR2. F. ILC1s secrete IFN-γ, ILC2s secrete IL-4, IL-5, and IL-13, and ILC3s secrete IL-17 and IL-22. Section references. 3‑1 After entering tissues, many microbes are recognized, ingested, and killed by phagocytes. Aderem, A., and Underhill, D.M.: Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 1999, 17:593–623. Auffray, C., Fogg, D., Garfa, M., Elain, G., Join-Lambert, O., Kayal, S., Sarnacki, S., Cumano, A., Lauvau, G., and Geissmann, F.: Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007, 317:666–670.


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