Immunology_Janeway

Immunology_Janeway. During the systemic phase of the infection, the T-cell response shifts to become focused on those antigens that enable the intracellular lifestyle of the pathogen. Some of these newly expressed antigens appear to activate cytosolic sensors within CD8α+ classical dendritic cells, which produce IL-12 to activate pathogen-specific TH1 cells and a type 1 response. The pathogen can now be cleared by TH1-induced macrophage activation directed against these newly expressed antigens. Because the anti-pathogen response now includes both type 3 and type 1 immunity to different sets of antigens that the bacterium requires for its extracellular and intracellular lifestyles, Salmonella is deprived of a niche for its survival and is cleared from the host. 11-14 Integration of celland antibody-mediated immunity is critical for protection against many types of pathogens.


Immunology_Janeway

Immunology_Janeway. The type of effector T cell or antibody required for host protection depends on the infectious strategy and lifestyle of the pathogen. As we learned in Chapter 9, cytotoxic T cells are important in destroying virus-infected cells, and in some viral diseases they are the predominant class of lymphocytes present in the blood during a primary infection. Nevertheless, the role of antibodies in clearing viruses from the body and preventing them from establishing another infection can be essential. Ebola virus causes a hemorrhagic fever and is one of the most lethal viruses known, but patients who do survive are protected and asymptomatic if they become infected again. In both the initial and recurrent infection, a strong, rapid antiviral IgG response against the virus is essential for survival. The antibody response clears the virus from the bloodstream and gives the patient time to activate cytotoxic T cells. This antibody response does not occur in infections that prove fatal; the virus


Immunology_Janeway

Immunology_Janeway. The antibody response clears the virus from the bloodstream and gives the patient time to activate cytotoxic T cells. This antibody response does not occur in infections that prove fatal; the virus continues to replicate, and even though there is activation of T cells, the disease progresses.


Immunology_Janeway

Immunology_Janeway. Cytotoxic T cells are also required for the destruction of cells infected with some intracellular bacterial pathogens, such as Rickettsia (the causative agent of typhus) or Listeria, which can escape from phagocytic vesicles to avoid the killing mechanisms of activated macrophages. In contrast, mycobacteria, which resist phagolysosomal killing and can live inside macrophage vesicles, are mainly kept in check by TH1 cells, which activate infected macrophages to kill the bacteria. Nevertheless, antibodies are induced in these infections and can contribute to pathogen killing when organisms are released from dying phagocytes, and are important in resistance to reinfection.


Immunology_Janeway

Immunology_Janeway. In many cases the most efficient protective immunity is mediated by neutralizing antibodies that can prevent pathogens from establishing an infection, and most of the established vaccines against acute childhood viral infections work primarily by inducing protective antibodies. Effective immunity against polio virus, for example, requires preexisting antibody, because the virus rapidly infects motor neurons and destroys them unless it is immediately neutralized by antibody and prevented from spreading within the body. In polio, specific IgA on mucosal epithelial surfaces also neutralizes the virus before it enters the tissues. Thus, protective immunity can involve effector mechanisms (IgA in this case) that do not operate in the elimination of the primary infection.


Immunology_Janeway

Immunology_Janeway. Fig. 11.20 Plasticity of CD4+ T-cell subsets. There is a hierarchy of stability of effector and regulatory CD4 T cells. Naive CD4+ T cells are multipotent, whereas TH1 and TH2 cells appear to be relatively stable, or at ‘ground state’; that is, they are highly resistant to transitioning into other effector cell phenotypes. iT cells and TH17 cells are less stable, and can transition into other subsets depending on prevailing cytokines. When acted on by IL-6 and IL-1, iT cells can transition into TH17 cells, or when acted on by IL-12 can become TH1 cells. TH17 cells acted on by IL-12 can transition into TH1 cells. Notably, the transitions of iT cells into TH17 cells, and TH17 cells into TH1 cells, appear to be unidirectional, or irreversible. Developing TH2 cells (left) repress expression of the inducible component of the IL-12 receptor (IL-12Rβ) and are unresponsive to IL-12; iTreg, TH17, and TH1 subsets (right) remain responsive to IL-12.


Immunology_Janeway

Immunology_Janeway. 11-15 Primary CD8 T-cell responses to pathogens can occur in the absence of CD4 T-cell help. Many CD8 T-cell responses are deficient in the absence of help from CD4 T cells (see Section 9-19). In such circumstances, CD4 T-cell help is required to activate dendritic cells for them to become able to stimulate a complete CD8 T-cell response, an activity that has been described as licensing of the antigen-presenting cell (see Section 9-10). Licensing involves the induction of co-stimulatory molecules such as B7, CD40, and 4-1BBL on the dendritic cell, which can then deliver signals that fully activate naive CD8 T cells (see Fig. 9.29). Licensing enforces a requirement for dual recognition of an antigen by the immune system by both CD4 and CD8 T cells, which provides a useful safeguard against autoimmunity. Dual recognition is also seen in the cooperation between T cells and B cells for antibody generation (see Chapter 10). However, not all CD8 T-cell responses require such help.


Immunology_Janeway

Immunology_Janeway. Some infectious agents, such as the intracellular Gram-positive bacterium Listeria monocytogenes and the Gram-negative bacterium Burkholderia pseudomallei, appear to be able to directly license dendritic cells to induce primary CD8 T-cell responses without requirement for CD4 T-cell help (Fig. 11.21). Primary CD8 T-cell responses to L. monocytogenes were examined in mice that were genetically deficient in MHC class II molecules and thus lacked CD4 T cells (see Section 11-23). The numbers of CD8 T cells specific for a particular antigen expressed by the pathogen were measured by using tetrameric peptide:MHC complexes, or peptide:MHC tetramers (see Appendix I, Section A-24), which can identify CD4 or CD8 T cells on the basis of the antigenic specificity of their T-cell receptors. On day 7 of infection, wild-type mice and mice lacking CD4 T cells showed equivalent expansion, and


Immunology_Janeway

Immunology_Janeway. Fig. 11.21 Naive CD8 T cells can be activated directly by potent antigen-presenting cells through their T-cell receptor or through the action of cytokines. Left panels: naive CD8 T cells that encounter peptide:MHC class I complexes on the surface of dendritic cells expressing high levels of co-stimulatory molecules as a result of the inflammatory environment produced by some pathogens (upper left panel) are activated to proliferate in response, eventually differentiating into cytotoxic CD8 T cells (lower left panel). Right panels: activated dendritic cells also produce the cytokines IL-12 and IL-18, whose combined effect on CD8 T cells rapidly induces the production of IFN-γ (upper right panel). This activates macrophages for the destruction of intracellular bacteria and can promote antiviral responses in other cells (lower right panel).


Immunology_Janeway

Immunology_Janeway. equivalent cytotoxic capacity, of pathogen-specific CD8 T cells. Mice lacking CD4 T cells cleared the initial infection by L. monocytogenes as effectively as wild-type mice. These experiments clearly show that protective responses can be generated by pathogen-specific CD8 T cells without CD4 T-cell help. However, as we will see later, the nature of the CD8 memory response is different and is diminished in the absence of CD4 T-cell help. Naive CD8 T cells can also undergo ‘bystander’ activation by IL-12 and IL-18 to produce IFN-γ very early during infection (see Fig. 11.21). Mice infected with


Immunology_Janeway

Immunology_Janeway. Naive CD8 T cells can also undergo ‘bystander’ activation by IL-12 and IL-18 to produce IFN-γ very early during infection (see Fig. 11.21). Mice infected with L. monocytogenes or B. pseudomallei rapidly produce a strong IFN-γ response, which is essential for their survival. The source of this IFN-γ seems to be both NK cells and naive CD8 T cells, which begin to secrete it within the first few hours after infection. This is believed to be too soon for any significant expansion of pathogen-specific CD8 T cells, which would initially be too rare to contribute in an antigen-specific manner. The production of IFN-γ by both NK and CD8 T cells at this early time can be blocked experimentally by antibodies against IL-12 and IL-18, suggesting that these cytokines are responsible. These experiments indicate that naive CD8 T cells can contribute nonspecifically in a kind of innate defense, one not requiring CD4 T cells, in response to early signals of infection.


Immunology_Janeway

Immunology_Janeway. 11-16 Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells.


Immunology_Janeway

Immunology_Janeway. When an infection is effectively repelled by the adaptive immune system, two things occur. First, the actions of effector cells remove the pathogen and, with them, the antigens that originally stimulated their differentiation. Second, in the absence of antigen, most effector T cells undergo ‘death by neglect,’ removing themselves by apoptosis. The resulting ‘clonal contraction’ of effector T cells appears to be due both to the loss of pro-survival cytokines that are produced by antigenic stimulation, such as IL-2, and to the loss of expression of receptors for these cytokines. CD25, the IL-2 receptor component that mediates high-affinity binding, is transiently upregulated on antigen-activated T cells, but then declines, thus limiting IL-2 signaling in the absence of antigenic restimulation. Also, as is discussed in Section 11-21, most effector T cells lose expression of the specific component of the IL-7 receptor IL-7Rα (CD127) soon after activation. Like IL-2 signaling, IL-7


Immunology_Janeway

Immunology_Janeway. Also, as is discussed in Section 11-21, most effector T cells lose expression of the specific component of the IL-7 receptor IL-7Rα (CD127) soon after activation. Like IL-2 signaling, IL-7 signaling activates STAT5, which promotes the expression of anti-apoptotic survival factors such as Bcl-2. Effector cells that lose responsiveness to IL-2 and IL-7 lose Bcl-2 and express Bim, which is a pro-apoptotic factor that acts via the intrinsic, or mitochondrial, pathway of apoptosis that leads to assembly of the apoptosome (see Sections 9-29 and 9-30).


Immunology_Janeway

Immunology_Janeway. While many effector T cells die from the loss of survival signals and the activation of the Bim-mediated intrinsic pathway of apoptosis, effector T-cell death can also occur via the extrinsic pathway of apoptosis that is activated by signaling via members of the TNF receptor superfamily, particularly Fas (CD95) (Fig. 11.22). Activation of the extrinsic pathway (or death receptor pathway) leads to the formation of the death-inducing signaling complex (DISC). The first step in Fas-mediated formation of the DISC is binding of the trimeric FasL, which results in the trimerization of Fas. This causes the death domains of Fas to bind to the death domain of FADD (Fas-associated via death domain), an adaptor protein introduced in Section 3-25. FADD contains a death domain and an additional domain called a death effector domain (DED) that can bind to DEDs present in other proteins. When FADD is recruited to Fas, the DED of FADD then recruits the initiator caspases pro-caspase 8 and pro-caspase


Immunology_Janeway

Immunology_Janeway. called a death effector domain (DED) that can bind to DEDs present in other proteins. When FADD is recruited to Fas, the DED of FADD then recruits the initiator caspases pro-caspase 8 and pro-caspase 10 via interaction with a DED in the pro-caspases. The high local concentration of these caspases in association with activated receptors allows the caspases to cleave themselves, resulting in their activation. Once activated, caspases 8 and 10 are released from the receptor complex and can activate the downstream


Immunology_Janeway

Immunology_Janeway. Fig. 11.22 Binding of Fas ligand to Fas initiates the extrinsic panel). FADD also contains a domain called a death effector domain pathway of apoptosis. The cell-surface receptor Fas contains (DED) that allows it to recruit pro-caspase 8 or pro-caspase 10, (not a so-called death domain (DD) in its cytoplasmic tail. When Fas shown), which also contains a DED domain (right panel). Clustered ligand (FasL) binds Fas, this trimerizes the receptor (left panel). The pro-caspase 8 activates itself to release an active caspase into the adaptor protein FADD (also known as MORT-1) also contains a death cytoplasm (not shown). domain and can bind to the clustered death domains of Fas (center effector caspases that induce apoptosis. Loss-of-function mutations in Fas lead to the increased survival of lymphocytes and are one cause of the disease autoimmune lymphoproliferative syndrome (ALPS). This disease can also be due to mutations in FasL and in caspase 10.


Immunology_Janeway

Immunology_Janeway. The relative contributions of the Bimand Fas-mediated apoptotic pathways to effector T-cell loss depend on the infectious agent, but they appear to be complementary mechanisms, as mice with specific deficiencies of Bim or Fas have milder defects in T-cell clearance than mice with deficiencies of both. Thus, the two pathways appear to be nonredundant; what aspects of infection contribute to the dominance of one mechanism over the other in response to different pathogens is unclear. Irrespective of whether their death is induced by the intrinsic or extrinsic pathway, dying T cells are rapidly cleared by phagocytes that recognize on their surface the membrane lipid phosphatidylserine. This lipid is normally found only on the inner surface of the plasma membrane, but in apoptotic cells it rapidly redistributes to the outer surface, where it can be recognized by specific receptors on many cells. Thus, not only is the pathogen removed at the end of infection, but most of the


Immunology_Janeway

Immunology_Janeway. cells it rapidly redistributes to the outer surface, where it can be recognized by specific receptors on many cells. Thus, not only is the pathogen removed at the end of infection, but most of the pathogen-specific effector cells are also removed. Some of the pathogen-specific effector cells survive, however, and provide the basis for memory T-cell and B-cell responses, as will be discussed in the next section.


Immunology_Janeway

Immunology_Janeway. Summary. CD4 T cells develop in response to, and subsequently amplify and sustain, innate immune responses that are induced by pathogens. Pathogen antigens are transported to local lymphoid organs by migrating dendritic cells and are presented to antigen-specific naive T cells that continuously recirculate through the lymphoid organs. T-cell priming and the differentiation of effector T cells occurs here, and the effector T cells either leave the lymphoid organ to provide cell-mediated immunity at sites of infection in the tissues or remain in the lymphoid organ to participate in humoral immunity by activating antigen-binding B cells. Distinct types of CD4 T cells develop in response to infection by different types of pathogens, and their development is influenced largely by the cytokines produced by innate sensor cells and ILCs that are activated early in the response.


Immunology_Janeway

Immunology_Janeway. Effector CD4 T cells serve to amplify and enhance early innate responses orchestrated by ILCs, while TFH cells that develop in concert with each subset of effector T cells direct the production of high-affinity antibodies that arm innate effector cells for heightened pathogen elimination. TH1 responses promote the development and activation of classical, M1 macrophages to protect against intracellular pathogens. TH2 responses are directed against infections by parasites such as helminths, and promote the development and activation of alternative, M2 macrophages and the recruitment of eosinophils and basophils to sites of infection. TH17 cells are integral to the clearance of extracellular bacteria and fungi, by orchestrating sustained neutrophil recruitment and production of antimicrobial peptides by epithelial cells of barrier tissues such as the intestines, lungs, and skin. CD8 T cells have an important role in protective immunity, especially in protecting the host against infection


Immunology_Janeway

Immunology_Janeway. peptides by epithelial cells of barrier tissues such as the intestines, lungs, and skin. CD8 T cells have an important role in protective immunity, especially in protecting the host against infection by viruses and intracellular infections by Listeria and other microbial pathogens that have special means for entering the host cell’s cytoplasm. Primary CD8 T-cell responses to pathogens usually require CD4 T-cell help, but can occur in response to some pathogens without such help. The patterns of anti-pathogenic response are not fixed, and effector T cells retain plasticity for adapting their response as pathogens alter their survival strategy in response to pressure from the immune system. Ideally, the adaptive immune response eliminates the infectious agent, at which time the expanded clonal populations of effector T cells contract, retaining only small populations of long-lived memory cells that provide the host with a state of protective immunity against reinfection with the same


Immunology_Janeway

Immunology_Janeway. populations of effector T cells contract, retaining only small populations of long-lived memory cells that provide the host with a state of protective immunity against reinfection with the same pathogen.


Immunology_Janeway

Immunological memory.

Immunology_Janeway. Immunological memory.


Immunology_Janeway

Immunology_Janeway. In this part of the chapter, we will examine how long-lasting protective immunity is maintained after an infection is successfully eliminated. Immunological memory is perhaps the most important consequence of an adaptive immune response, because it enables the immune system to respond more rapidly and effectively to pathogens that have been encountered previously, and prevents them from causing disease. Memory responses, called secondary immune responses, tertiary immune responses, and so on, depending on the number of exposures to antigen, also differ qualitatively from primary responses. This is particularly clear for B-cell responses, in that antibodies made during secondary and subsequent responses exhibit distinct characteristics, such as higher affinity to antigen compared with antibodies made during the primary response. Memory T-cell responses can also be distinguished qualitatively from the responses of naive or effector T cells, in terms of location, trafficking patterns,


Immunology_Janeway

Immunology_Janeway. made during the primary response. Memory T-cell responses can also be distinguished qualitatively from the responses of naive or effector T cells, in terms of location, trafficking patterns, and effector functions.


Immunology_Janeway

Immunology_Janeway. 11-17 Immunological memory is long lived after infection or vaccination. Most children in developed countries are now vaccinated against measles virus; before vaccination was widespread, most were naturally exposed to this virus and developed an acute, unpleasant, and potentially dangerous illness. Whether through vaccination or infection, children exposed to the virus acquire long-term protection from measles, lasting for most people for the whole of their life. The same is true of many other acute infectious diseases (see Chapter 16): this state of protection is a consequence of immunological memory.


Immunology_Janeway

Immunology_Janeway. Because smallpox has been eradicated, recall responses measured in people who were vaccinated for smallpox can be taken to represent true memory in the absence of reinfection. After smallpox vaccination, antibody levels show an early peak with a period of rapid decay, which is followed by long-term maintenance that shows no significant decay. CD4 and CD8 T-cell memory is long lived but gradually decays, with a half-life in the range of 8–15 years.


Immunology_Janeway

Immunology_Janeway. The basis of immunological memory has been difficult to explore experimentally. Although the phenomenon was first recorded by the ancient Greeks and has been exploited routinely in vaccination programs for more than 200 years, it was recognized only within the last 30 years that this memory phenomenon reflects a small population of specialized memory cells that are formed during the adaptive immune response and can persist in the absence of the antigen that originally induced them. This mechanism of maintaining memory is consistent with the finding that only individuals who were themselves previously exposed to a given infectious agent are immune. The idea that immunological memory does not depend on repeated exposure to infection as a result of contact with other infected individuals has been supported by observations made of populations of people living on remote islands. In that setting, a virus such as measles can cause an epidemic, infecting all people living on the island at


Immunology_Janeway

Immunology_Janeway. has been supported by observations made of populations of people living on remote islands. In that setting, a virus such as measles can cause an epidemic, infecting all people living on the island at that time, after which the virus disappears for many years. On reintroduction from outside the island, the virus does not affect the original population but causes disease in those people born since the first epidemic.


Immunology_Janeway

Immunology_Janeway. The duration of immunological memory has been estimated by examining responses in people who received vaccinia, the virus used to immunize against smallpox (Fig. 11.23). Because smallpox was eradicated in 1978, it is presumed that their responses represent true immunological memory and are not due to restimulation from time to time by the smallpox virus. One study found strong vaccinia-specific CD4 and CD8 T-cell memory responses as long as 75 years after the original immunization, and from the strength of these responses it was estimated that the memory response had an approximate half-life of between 8 and 15 years. Half-life represents the time required for a response to diminish to 50% of its original strength. By contrast with T-cell memory, titers of antivirus antibody remained stable, almost without measurable decline.


Immunology_Janeway

Immunology_Janeway. These findings show that immunological memory need not be maintained by repeated exposure to infectious virus. Instead, it is likely that memory is sustained by long-lived antigen-specific lymphocytes that were induced by the original exposure and that persist until a second encounter with the pathogen. Although most of the memory cells are in a resting state, a small percentage of memory cells are dividing at any one time. It appears that this turnover is maintained by cytokines, such as IL-7 and IL-15, produced either constitutively or during antigen-specific immune responses directed at other, non-cross-reactive antigens. The number of memory cells for a given antigen is highly regulated, persisting with a relatively long half-life balanced by cell proliferation and cell death.


Immunology_Janeway

Immunology_Janeway. Immunological memory can be measured experimentally in various ways. Adoptive transfer assays (see Appendix I, Section A-30) of lymphocytes from animals immunized with simple, nonliving antigens have been favored for such studies, because the antigen cannot proliferate. In these experiments, the existence of memory cells is measured purely in terms of the transfer of specific responsiveness from an immunized, or ‘primed,’ animal to a nonimmunized recipient, as tested by a subsequent immunization with the antigen. Animals that received memory cells have a faster and more robust response to antigen challenge than do controls that did not receive cells, or that received cells from nonimmune donors.


Immunology_Janeway

Immunology_Janeway. Experiments like these have shown that when an animal is first immunized with a protein antigen, functional helper T-cell memory against that antigen appears abruptly and reaches a maximum after 5 days or so. Functional antigen-specific B-cell memory appears some days later, then enters a phase of cell proliferation and selection in lymphoid tissues. By 1 month after immunization, memory B cells are present at their maximum level. These levels of memory cells are then maintained, with little alteration, for the lifetime of the animal. It is important to recognize that the functional memory elicited in these experiments can be due to the precursors of memory cells as well as the memory cells themselves. These precursors are probably activated T cells and B cells, some of whose progeny will later differentiate into memory cells. Thus, precursors to memory cells can appear very shortly after immunization, even though resting memory-type lymphocytes may not yet have developed.


Immunology_Janeway

Immunology_Janeway. In the following sections we look in more detail at the changes that occur in lymphocytes after antigen priming and lead to the development of resting memory lymphocytes, and discuss the mechanisms that might account for these changes. 11-18 Memory B-cell responses are more rapid and have higher affinity for antigen compared with responses of naive B cells.


Immunology_Janeway

Immunology_Janeway. Immunological memory in B cells can be examined in vitro by isolating B cells from immunized or unimmunized mice and restimulating them with antigen in the presence of helper T cells specific for the same antigen (Fig. 11.24). B cells from immunized mice produce responses that differ both quantitatively and qualitatively compared with naive B cells from unimmunized mice. B cells that respond to the antigen increase in frequency by up to 100-fold after their initial priming in the primary immune response. Further, due to the process of affinity maturation (described in Chapter 10), antibodies produced by B cells of immunized mice typically have higher affinity for antigen than antibodies produced by unprimed B lymphocytes. The response from immunized mice is due to memory B cells that arise in the primary response. Memory B cells can arise from the germinal center reaction during a primary response, and may have undergone isotype switching and somatic mutations there. But memory B


Immunology_Janeway

Immunology_Janeway. arise in the primary response. Memory B cells can arise from the germinal center reaction during a primary response, and may have undergone isotype switching and somatic mutations there. But memory B cells can also arise independently of the germinal center reaction from short-lived plasma cells produced in the primary response. In either case, they circulate through the blood and take up residence in the spleen and lymph nodes. Memory B cells express some markers that distinguish them from naive B cells and plasma cells. One marker of memory B cells is simply


Immunology_Janeway

Immunology_Janeway. Fig. 11.24 The generation of secondary antibody responses from memory B cells is distinct from the generation of the primary antibody response. These responses can be studied and compared by isolating B cells from immunized and unimmunized donor mice, and stimulating them in culture in the presence of antigen-specific effector T cells. The primary response usually consists of antibody molecules made by plasma cells derived from a quite diverse population of precursor B cells specific for different epitopes of the antigen and with receptors that have a range of affinities for the antigen. The antibodies are of relatively low affinity overall, with few somatic mutations. The secondary response derives from a far more limited population of high-affinity B cells, which have, however, undergone significant clonal expansion. Their receptors and antibodies are of high affinity for the antigen and show extensive somatic mutation. The overall effect is that although there is usually only a


Immunology_Janeway

Immunology_Janeway. significant clonal expansion. Their receptors and antibodies are of high affinity for the antigen and show extensive somatic mutation. The overall effect is that although there is usually only a 10to 100-fold increase in the frequency of activatable B cells after priming, the quality of the antibody response is radically altered, in that these precursors induce a far more intense and effective response.


Immunology_Janeway

10,000 100 10 1 0.1 0.01

Immunology_Janeway. 10,000 100 10 1 0.1 0.01


Immunology_Janeway

Immunology_Janeway. Fig. 11.25 Both the affinity and the amount of antibody increase with repeated immunization. The upper panel shows the increase in antibody concentration with time after a primary (1°), followed by a secondary (2°) and a tertiary (3°), immunization; the lower panel shows the increase in the affinity of the antibodies (affinity maturation). Affinity maturation is seen largely in IgG antibody (as well as in IgA and IgE, which are not shown) coming from mature B cells that have undergone isotype switching and somatic hypermutation to yield higher-affinity antibodies. The blue shading represents IgM on its own, the yellow shading IgG, and the green shading the presence of both IgG and IgM. Although some affinity maturation occurs in the primary antibody response, most arises in later responses to repeated antigen injections. Note that these graphs are on a logarithmic scale; it would otherwise be impossible to represent the overall increase of around 1 millionfold in the concentration of


Immunology_Janeway

Immunology_Janeway. to repeated antigen injections. Note that these graphs are on a logarithmic scale; it would otherwise be impossible to represent the overall increase of around 1 millionfold in the concentration of specific IgG antibody from its initial level.


Immunology_Janeway

Immunology_Janeway. the expression of a switched surface immunoglobulin isotype, compared with naive B cells that express surface IgM and IgD. In contrast, plasma cells have very low surface immunoglobulin altogether. In humans, a marker of memory B cells is CD27, a member of the TNF receptor family that is also expressed by naive T cells and binds the TNF-family ligand CD70, which is expressed by dendritic cells (see Section 9-17).


Immunology_Janeway

Immunology_Janeway. A primary antibody response is characterized by the initial rapid production of IgM and a slightly delayed IgG response due to time required for class switching (Fig. 11.25). The secondary antibody response is characterized in its first few days by the production of relatively small amounts of IgM antibody and much larger amounts of IgG antibody, with some IgA and IgE. At the beginning of the secondary response, antibodies are made by memory B cells that were generated in the primary response and have already switched from IgM to another isotype, and that express IgG, IgA, or IgE on their surface. Memory B cells express somewhat higher levels of MHC class II molecules and the co-stimulatory ligand B7.1 than do naive B cells. This helps memory B cells acquire and present antigen more efficiently to TFH cells compared with naive B cells, and to TFH cells through the B7.1 receptor CD28, so that they can in turn help in antibody production so it begins earlier after antigen exposure


Immunology_Janeway

Immunology_Janeway. efficiently to TFH cells compared with naive B cells, and to TFH cells through the B7.1 receptor CD28, so that they can in turn help in antibody production so it begins earlier after antigen exposure compared with primary responses. The secondary response is characterized by a more vigorous and earlier generation of plasma cells than in the primary response, thus accounting for the almost immediate abundant production of IgG (see Fig. 11.25).


Immunology_Janeway

Immunology_Janeway. during secondary immune responses. During a secondary exposure to infection, antibodies persisting from a primary immune response are available immediately to bind the pathogen and mark it for degradation by complement or by phagocytes. If the antibody can completely neutralize the pathogen, a secondary immune response may not occur. Otherwise, excess antigens will bind to receptors on B cells and initiate a secondary response in the peripheral lymphoid organs. Memory B cells recirculate through the same secondary lymphoid compartments as naive B cells, principally the follicles of the spleen, lymph nodes, and the Peyer’s patches of the gut mucosa. B cells with the highest avidity for antigen are activated first. Thus memory B cells, which have been selected previously for their avidity to antigen, make up a substantial component of the secondary response.


Immunology_Janeway

Immunology_Janeway. Besides responding more rapidly, memory B cells can reenter germinal centers during secondary immune responses and undergo additional somatic hypermutation and affinity maturation, as described in Sections 10-6 through 10-8. As in primary responses, secondary B-cell responses begin at the interface between the T-cell and B-cell zones, where memory B cells that have acquired antigen can present peptide:MHC class II complexes to helper T cells. This interaction initiates proliferation of both the B cells and T cells.


Immunology_Janeway

Immunology_Janeway. Reactivated memory B cells that have not yet undergone differentiation into plasma cells migrate into the follicle and become germinal center B cells, undergoing additional rounds of proliferation and somatic hypermutation before differentiating into antibody-secreting plasma cells. Since B cells with the higher-affinity antigen receptors will more efficiently acquire and present antigen to antigen-specific TFH cells in the germinal center, the affinity of the antibodies produced during secondary and tertiary responses rises progressively (see Fig. 10.14). increased frequency relative to their frequency as naive T cells.


Immunology_Janeway

Immunology_Janeway. increased frequency relative to their frequency as naive T cells. Until relatively recently, analysis of T-cell memory relied on assays of T-cell function rather than a direct identification of antigen-specific memory T cells. Some assays of T-cell effector function, such as providing help to B cells or macrophages, can take several days to perform. Because of this, such assays are not optimal for distinguishing memory T cells from preexisting effector cells, since memory cells can be reactivated during the time frame of the assay. This is a problem particularly for effector CD4 T cells, but does not apply as much for effector CD8 T cells, which can program a target cell for lysis in 5 minutes. In contrast, memory CD8 T cells need more time than this to be reactivated to become cytotoxic, so that the actions of memory CD8 T cells will appear much later than those of preexisting effector cells.


Immunology_Janeway

Immunology_Janeway. Examining T-cell memory has been made easier by the development of MHC tetramers (see Appendix I, Section A-24). Before MHC tetramers, effector and memory responses were studied using naive T cells from mice carrying specific T-cell receptor (TCR) transgenes. Such TCR-transgenic T cells could be uniquely identified by antibodies to their rearranged T-cell receptors, but were not part of the host’s natural T-cell repertoire. MHC tetramers measure the in vivo frequency of all clones with a given antigen specificity, but do not distinguish between different T-cell clones of the same specificity. MHC tetramers were generated for MHC class I molecules first, but are now also available for some MHC class II molecules, allowing the study of both CD8 and CD4 T cells both in normal mice and in humans.


Immunology_Janeway

Immunology_Janeway. MHC tetramers have allowed a direct analysis of the formation of memory T cells. In the example shown in Fig. 11.26, T-cell responses to infection by the intracellular bacteria Listeria monocytogenes are analyzed with MHC class II tetramers specific to the toxin listeriolysin O (LLO). In the naive T-cell repertoire of the mouse, there are approximately 100 LLO-specific CD4 T cells, which undergo 1000-fold expansion into effector T cells during the Fig. 11.26 Generation of memory T cells expansion phase of 6 days after infection. When the infection is eliminated, after an infection. After an infection, in this case with an attenuated strain of Listeria


Immunology_Janeway

Immunology_Janeway. LLOp:I-Ab+ 106 106 cells 105 105 104 104 103 103 102 102 101 monocytogenes, the number of T cells specific for the listeriolysin (LLO) toxin increases dramatically and then falls back to give a sustained low level of memory T cells. T-cell responses are detected by binding of an MHC tetramer consisting of an LLO peptide bound by I-Ab. The left panel shows the primary response of CD4 T cells that are LLO-specific, and the right panel shows the contraction and memory phase. Approximately 100 T cells in the naive T-cell repertoire expand to about 100,000 effector cells by day 7, and then contract to about 7000 memory cells by day 25. These memory cells then slowly decay to 500 cells by day 450. Data courtesy of Marc Jenkins.


Immunology_Janeway

Immunology_Janeway. a slower contraction phase follows in which these T cells are reduced by about 100-fold within a few weeks. This leaves a population of memory T cells present at a frequency of about 10-fold higher than in the naive repertoire, and this population persists with a half-life of about 60 days. 11-21 Memory T cells arise from effector T cells that maintain sensitivity to IL-7 or IL-15.


Immunology_Janeway

Immunology_Janeway. 11-21 Memory T cells arise from effector T cells that maintain sensitivity to IL-7 or IL-15. Naive and memory T cells can be distinguished by differences in their expression of various cell-surface proteins, by their distinct responses to stimuli, and by their expression of certain genes. Overall, memory cells continue to express many markers of activated T cells, such as phagocytic glycoprotein-1 (Pgp1, CD44), but they stop expressing other activation markers, such as CD69. Memory T cells express more Bcl-2, a protein that promotes cell survival and may be responsible for their long half-life. Figure 11.27 lists several molecules by which naive, effector, and memory T cells can be distinguished.


Immunology_Janeway

Immunology_Janeway. Fig. 11.27 Expression of many proteins alters when naive T cells become memory T cells. Proteins that are expressed differently in naive T cells, effector T cells, and memory T cells include adhesion molecules, which govern interactions with antigen-presenting cells and endothelial cells; chemokine receptors, which affect migration to lymphoid tissues and sites of inflammation; proteins and receptors that promote the survival of memory cells; and proteins that are involved in effector functions, such as granzyme B. Some changes also increase the sensitivity of the memory T cell to antigen stimulation. Many of the changes that occur in memory T cells are also seen in effector cells, but some, such as expression of the cell-surface proteins CD25 and CD69, are specific to effector T cells; others, such as expression of the survival factor Bcl-2, are limited to long-lived memory T cells. This list represents a general picture that applies to both CD4 and CD8 T cells in mice and humans,


Immunology_Janeway

Immunology_Janeway. others, such as expression of the survival factor Bcl-2, are limited to long-lived memory T cells. This list represents a general picture that applies to both CD4 and CD8 T cells in mice and humans, but some details that may differ between these sets of cells have been omitted for simplicity.


Immunology_Janeway

Immunology_Janeway. Days after transfer 1470 0 Mice infected with LCMV generate a primary CD8 response; some effector cells express high levels of IL-7R˜, while others do not Only transfer of the IL-7R˜hi-CD8 T cells into naive mice led to robust expansion of antigen-specifc CD8 cells after secondary challenge LCMV TCR-transgenic mouse naive mice antigen challenge Number of antigen-specifcCD8 T cells antigen challenge CD8 IL-7R˜hi cells transfer transfer IL-7R˜lo cells


Immunology_Janeway

Immunology_Janeway. Fig. 11.28 Expression of the IL-7 receptor (IL- 7Rα) indicates which CD8 effector T cells can generate robust memory responses. Mice expressing a T-cell receptor (TCR) transgene specific for a viral antigen from lymphocytic choriomeningitis virus (LCMV) were infected with the virus, and effector cells were collected on day 11. Effector CD8 T cells expressing high levels of IL-7Rα (IL-7Rαhi, blue) were separated and transferred into one group of naive mice, and effector CD8 T cells expressing low IL-7Rα (IL-7Rαlo, green) were transferred into another group. Three weeks after transfer, the mice were challenged with a bacterium engineered to express the original viral antigen, and the numbers of responding transferred T cells (detected by their expression of the transgenic TCR) were measured at various times after challenge. Only the transferred IL-7Rαhi effector cells could generate a robust expansion of CD8 T cells after the secondary challenge.


Immunology_Janeway

Immunology_Janeway. Among the important markers of memory T cells is the α subunit of the IL-7 receptor (IL-7Rαor CD127). Naive T cells express IL-7Rα, but it is rapidly lost upon activation and is not expressed by most effector T cells. For example, the experiment shown in Fig. 11.28 examines mice infected with lymphocytic choriomeningitis virus (LCMV). Around day 7 after infection, a small population of approximately 5% of CD8 effector T cells expressed high levels of IL-7Rα. Adoptive transfer of these IL-7Rαhi cells, but not IL-7Rαlo effector T cells, could provide functional CD8 T-cell memory to uninfected mice. This experiment suggests that memory T cells arise from effector T cells that maintain or reexpress IL-7Rα, perhaps because they compete more effectively for the survival signals delivered by IL-7.


Immunology_Janeway

Immunology_Janeway. The homeostatic mechanisms governing the survival of memory T cells also differ from those for naive T cells. Memory T cells divide more frequently than naive T cells, and their expansion is controlled by a shift in the balance between proliferation and cell death. As illustrated in Fig. 11.29, naive T cells require contact with self peptide:self MHC complexes in addition to cytokine stimulation for their long-term survival in the periphery (see Fig. 9.4). As with naive cells, the survival of memory T cells requires signaling by the receptors for the cytokines IL-7 and IL-15. IL-7 is required for the survival of both CD4 and CD8 memory T cells. In addition, IL-15 is critical for the long-term survival and proliferation of CD8 memory T cells under normal conditions. It also appears that memory T cells are less dependent on contact with self peptide:self MHC than naive T cells and are more sensitive to cytokines.


Immunology_Janeway

Immunology_Janeway. Memory T cells still require contact with peptide:MHC complexes to become reactivated during a secondary encounter with pathogen, but are also more sensitive to restimulation by antigen than are naive T cells. Furthermore, they more quickly and more vigorously produce several cytokines such as IFN-γ, TNF-α, and IL-2 in response to such stimulation. A similar progression occurs for T cells in humans after immunization with a vaccine against yellow fever virus.


Immunology_Janeway

Immunology_Janeway. For their survival in the periphery, naive T cells require periodic stimulation with the cytokines IL-7 and IL-15 and with self-antigens presented by self MHC molecules. On priming with its specific antigen, a naive T cell divides and differentiates. Most of the progeny differentiate into relatively short-lived effector cells that have lost expression of the IL-7 receptor (yellow), but some effector cells retain or reexpress the receptor and become long-lived memory T cells. These memory cells can be maintained by IL-7 and IL-15 and are less dependent on contact with self peptide:self MHC complexes for survival compared with naive T cells. However, contact with self antigens may be necessary for some memory T cells to keep up their numbers in the memory pool, but this may vary between different clones and is the subject of ongoing investigation. 11-22 Memory T cells are heterogeneous and include central memory, effector memory, and tissue-resident subsets.


Immunology_Janeway

Immunology_Janeway. Changes in other cell-surface proteins that occur on memory CD4 T cells after exposure to antigen are significant (see Fig. 11.27). L-selectin (CD62L) is the homing receptor that directs T cells into secondary lymphoid tissues, and it is lost by effector cells and most memory CD4 T cells. CD44 is a receptor for hyaluronic acid and other ligands expressed in peripheral tissues, and it is induced on effector and memory T cells. The change in expression of these two molecules helps memory T cells migrate from the blood into the peripheral tissues rather than migrating directly into lymphoid tissues, as would naive T cells. Different isoforms of CD45, a cell-surface protein tyrosine phosphatase expressed on all hematopoietic cells, are useful in distinguishing naive from effector and memory T cells. The CD45RO isoform is produced because of changes in the alternative splicing of exons that encode the CD45 extracellular domain and identifies effector and memory cells, although it is


Immunology_Janeway

Immunology_Janeway. T cells. The CD45RO isoform is produced because of changes in the alternative splicing of exons that encode the CD45 extracellular domain and identifies effector and memory cells, although it is unclear what functional consequences this change may impose. Some surface receptors, such as CD25, the α subunit of the IL-2 receptor, are expressed on activated effector cells, but not memory cells; however, they can be reexpressed when memory cells are again reactivated by antigen and become effector T cells.


Immunology_Janeway

Immunology_Janeway. Memory T cells are heterogeneous, and both CD4 and CD8 T cells are classified into three major subsets. Each type exhibits a distinct pattern of receptors, for example, for different chemokines and adhesion molecules, and shows different activation characteristics (Fig. 11.30). Central memory T cells (TCM) express the chemokine receptor CCR7, which allows their recirculation to be similar to that of naive T cells and allows them to traffic through the T-cell zones of peripheral lymphoid tissues. Central memory cells are very sensitive to cross-linking of their T-cell receptors and rapidly express CD40 ligand in response; however, they are relatively slower compared with other memory subsets to acquire effector functions such as production of cytokines early after restimulation. Central memory cells primarily migrate from the blood, into the secondary lymphoid organs, then into the lymphatic system and back into the blood, a route very similar to the migration pattern of naive T cells.


Immunology_Janeway

Immunology_Janeway. cells primarily migrate from the blood, into the secondary lymphoid organs, then into the lymphatic system and back into the blood, a route very similar to the migration pattern of naive T cells. By contrast, effector memory T cells (TEM) lack the chemokine receptor CCR7, but express high levels of β1 and β2 integrins, and so are specialized for rapidly entering inflamed tissues. They also express receptors for inflammatory chemokines and can rapidly mature into effector T cells and secrete large amounts of IFN-γ, IL-4, and IL-5 early after restimulation. Effector memory T cells migrate from the blood primarily into peripheral nonlymphoid tissues, then through the lymphatic system and finally into secondary lymphoid tissues. There they can reenter the lymphatic system and reach the blood again. In contrast to central and effector memory cells, tissue-resident memory T cells (TRM) comprise a substantial fraction of memory T cells that do not migrate, but rather take up long-term


Immunology_Janeway

Immunology_Janeway. blood again. In contrast to central and effector memory cells, tissue-resident memory T cells (TRM) comprise a substantial fraction of memory T cells that do not migrate, but rather take up long-term residency in various epithelial sites (Fig. 11.31). Like TEM cells, TRM cells lack CCR7 but express other chemokine receptors (for example, CXCR3, CCR9) that allow migration into peripheral tissues such as the dermis or the lamina propria of the intestine. In these sites, TRM cells induce CD69, which


Immunology_Janeway

Immunology_Janeway. CD45RO CCR3 CCR5 Effector memory cells lack CCR7 and migrate to tissues CCR7 Central memory cells express CCR7 and remain in lymphoid tissue CD45RO Most effector cells die after a few days Some effector cells may become quiescent memory cells Memory cells derive directly from some effector T cells CD45RO IL-7R˜Effector T cells differentiate, secrete cytokines, and express cytokine receptors IL-4 IL-2 perforin FasL Naive T cell sees antigen T dendritic cell CD45RACCR7 Fig. 11.30 T cells differentiate into central memory and effector memory subsets, which are distinguished by the expression of the chemokine receptor CCR7.


Immunology_Janeway

Immunology_Janeway. Fig. 11.30 T cells differentiate into central memory and effector memory subsets, which are distinguished by the expression of the chemokine receptor CCR7. Quiescent memory cells bearing the characteristic CD45RO surface protein can arise from activated effector cells (right half of diagram) or directly from activated naive T cells (left half of diagram). Two types of quiescent memory T cells can derive from the primary T-cell response: central memory cells and effector memory cells. Central memory cells express CCR7 and remain in peripheral lymphoid tissues after restimulation. Memory cells of the other type—effector memory cells—mature rapidly into effector T cells after restimulation, and secrete large amounts of IFN-γ, IL-4, and IL-5. They do not express the receptor CCR7, but express receptors (CCR3 and CCR5) for inflammatory chemokines.


Immunology_Janeway

Immunology_Janeway. reduces S1PR expression, thereby promoting retention in tissues. TRM cells, particularly CD8 TRM cells, enter and reside within the epithelium. TGF-βproduction by epithelial cells induces TRM cells to express the integrin αE:β7, which binds E-cadherin expressed by epithelium and is required for TRM retention. The distinction between TCM, TEM, and TRM memory populations has been made both in humans and in the mouse. However, each subset itself is not strictly a homogeneous population. For example, within the CCR7-expressing TCM cells, there are cells with differing expression of other markers, particularly chemokine receptors. A subset of the CCR7-positive TCM cells also express CXCR5, similarly to TFH cells, although it is not yet clear whether these memory cells can provide help to B cells in the germinal center.


Immunology_Janeway

Immunology_Janeway. On stimulation by antigen, TCM cells rapidly lose expression of CCR7 and differentiate into TEM cells. TEM cells are also heterogeneous in the chemokine receptors they express, and have been classified according to chemokine receptors typical of TH1 cells (CCR5), TH17 cells (CCR6), and TH2 cells (CCR4). Central memory cells do not appear committed to particular effector lineages,


Immunology_Janeway

Immunology_Janeway. Fig. 11.31 Tissue-resident memory T cells are a major immune compartment that surveys peripheral tissues for reinfection by pathogens. After activation and priming in lymphoid tissues, activated CD8 and CD4 T cells enter the blood and enter tissues in response to various chemokines, as shown here for entry into the dermis, guided by expression of CXCR3. The reexpression of CD69 by T cells caused by antigen or other unknown signals leads to decreased S1PR1 surface expression, promoting retention of these cells in the dermis. In response to TGF-β, some cells induce integrin αE:β7 (CD103), which binds E-cadherin expressed by epithelial cells, promoting entry and retention of T cells in the epidermis, where many CD8 TRM cells reside. Recent estimates indicate that TRM cells may outnumber the recirculating T cells that migrate through the body.


Immunology_Janeway

Immunology_Janeway. and even effector memory cells are not fully committed to the TH1, TH17, or TH2 lineage, although there is some correlation between their eventual output of TH1, TH17, or TH2 cells and the chemokine receptors expressed. Further stimulation with antigen seems to drive the differentiation of effector memory cells gradually into the distinct effector T-cell lineages. 11-23 CD4 T-cell help is required for CD8 T-cell memory and involves CD40 and IL-2 signaling.


Immunology_Janeway

Immunology_Janeway. There is experimental evidence that CD4 T cells play an important role in programming optimal CD8 T-cell memory. In the experiment shown in Fig. 11.32, the primary and memory CD8 T-cell responses were compared between wild-type mice and mice that lack expression of MHC class II, and which therefore have a defect in CD4 T cells. In this experiment, the CD8 T-cell response was measured against a protein, ovalbumin, carried by an experimental strain of Listeria monocytogenes. After 7 days of infection, both types of mice showed equivalent expansion and activity of antigen-specific CD8 effector T cells. But mice with a defect in CD4 T cells generated much weaker secondary responses, characterized by the presence of far fewer expanding memory CD8 T cells after a secondary challenge. These results imply a role for CD4 T cells either in the initial programming of CD8 T cells or during the secondary memory response.


Immunology_Janeway

Immunology_Janeway. Further experiments suggest that this CD4 T-cell help is necessary for the initial programming of naive CD8 T cells. Memory CD8 T cells that developed in the absence of CD4 help were transferred into wild-type mice. After transfer, the recipient mice were challenged again, whereupon the CD8 T cells showed a reduced ability to proliferate even though the recipient mice expressed MHC class II. This result indicates that CD4 T-cell help is required during the priming of CD8 T cells and not simply at the time of secondary responses.


Immunology_Janeway

Immunology_Janeway. Fig. 11.32 CD4 T cells are required for the development of functional CD8 memory T cells. Mice that do not express MHC class II molecules (MHC II–/–) fail to develop CD4 T cells. Wild-type and MHC II–/– mice were infected with Listeria monocytogenes expressing the model antigen ovalbumin (LM-OVA). After 7 days, the number of OVA-specific CD8 T cells can be measured by using specific MHC tetramers that contain an OVA peptide, and therefore bind to T-cell receptors that react with this antigen. After 7 days of infection, mice lacking CD4 T cells were found to have the same number of OVA-specific CD8 T cells as wild-type mice. However, when mice were allowed to recover for 60 days—a time during which memory T cells could develop—and were then re-challenged with LM-OVA, the mice lacking CD4 T cells failed to expand CD8 memory cells specific to OVA, whereas there was a strong CD8 memory response in the wild-type mice.


Immunology_Janeway

Immunology_Janeway. This requirement for CD4 help in CD8 memory generation has also been demonstrated by experiments in which CD4 T cells were depleted by treatment with antibody or in which mice were deficient in the CD4 gene. The mechanism underlying this requirement for CD4 T cells is not completely understood. It may involve two types of signals received by the CD8 T cell— those received through CD40 and those received through the IL-2 receptor. CD8 T cells that do not express CD40 are unable to generate memory T cells. Although many cells could potentially express the CD40 ligand needed to stimulate CD40, it is most likely that CD4 T cells are the source of this signal.


Immunology_Janeway

Immunology_Janeway. The requirement for IL-2 signaling in programming CD8 memory was discovered by using CD8 T cells that were unable to respond to IL-2 because of a genetic deficiency in the IL-2Rα subunit. Because IL-2Rα signaling is required for the development of T cells, mice lacking IL-2Rα develop a lymphopro liferative disorder. However, this disorder does not develop in mice that are mixed bone marrow chimeras harboring both wild-type and IL-2Rα-deficient cells, and these chimeras can be used to study the behavior of IL-2Rα-deficient cells. When these chimeric mice were infected with LCMV and their responses were tested, memory CD8 responses were found to be defective specifically in the T cells lacking IL-2Rα.


Immunology_Janeway

Immunology_Janeway. The experiment shown in Fig. 11.33 indicates that, distinct from their effect in programming naive CD8 T cells, CD4 T cells also provide help in maintaining the number of CD8 memory T cells. In this case, CD8 memory T cells that had been programmed in normal mice were transferred into immunologically naive mice that either expressed or lacked MHC class II. Transfer of CD8 memory cells into mice lacking MHC class II resulted in a more rapid decrease in the number of memory CD8 T cells in comparison with a similar transfer


Immunology_Janeway

Immunology_Janeway. Fig. 11.33 CD4 T cells promote the maintenance of CD8 memory cells. The dependence of memory CD8 T cells on CD4 T cells is shown by the different lifetimes of the memory cells after their transfer into host mice that either have normal CD4 T cells (wildtype) or lack CD4 T cells (MHC II–/–). In the absence of MHC class II proteins, CD4 T cells fail to develop in the thymus. When CD8 memory T cells specific for LCMV were isolated from donor mice 35 days after infection with the virus and transferred into these hosts, memory cells were maintained only in mice that had CD4 T cells. The basis for this action of CD4 T cells is not yet clear, but has implications for conditions such as HIV/AIDS in which the number of CD4 T cells is diminished.


Immunology_Janeway

Immunology_Janeway. into wild-type mice. In addition, CD8 effector cells transferred into mice lacking MHC class II had a relative impairment of CD8 effector functions. These experiments imply that CD4 T cells activated by MHC class II-expressing antigen-presenting cells during an immune response have a significant impact on the quantity and quality of the CD8 T-cell response, even when they are not needed for the initial CD8 T-cell activation. CD4 T cells help to program naive CD8 T cells to be able to generate memory T cells, help to promote efficient effector activity, and help to maintain memory T-cell numbers. 11-24 In immune individuals, secondary and subsequent responses are mainly attributable to memory lymphocytes.


Immunology_Janeway

Immunology_Janeway. 11-24 In immune individuals, secondary and subsequent responses are mainly attributable to memory lymphocytes. In the normal course of an infection, a pathogen proliferates to a level sufficient to elicit an adaptive immune response and then stimulates the production of antibodies and effector T cells that eliminate the pathogen from the body. Most of the effector T cells then die, and antibody levels gradually decline, because the antigens that elicited the response are no longer present at the level needed to sustain it. We can think of this as feedback inhibition of the response. Memory T and B cells remain, however, and maintain a heightened ability to mount a response to a recurrence of infection with the same pathogen.


Immunology_Janeway

Immunology_Janeway. Antibody and memory lymphocytes remaining in an immunized individual can have the effect of reducing the activation of naive B and T cells on a subsequent encounter with the same antigen. In fact, passively transferring antibody to a naive recipient can be used to inhibit naive B-cell responses to that same antigen. This phenomenon has been put to practical use to prevent Rh– mothers from making an immune response to an Rh+ fetus, which can result in hemolytic disease of the newborn (see Appendix I, Section A-6). If anti-Rh antibody is given to the mother before she is first exposed to her child’s Rh+ red blood cells, her response will be inhibited. The mechanism of this suppression is likely to involve the antibody-mediated clearance and destruction of fetal red blood cells that have entered the mother, thus preventing naive B cells and T cells from mounting an immune response. Presumably, the anti-Rh antibody is in excess over antigen, so that not only is antigen eliminated, but


Immunology_Janeway

Immunology_Janeway. entered the mother, thus preventing naive B cells and T cells from mounting an immune response. Presumably, the anti-Rh antibody is in excess over antigen, so that not only is antigen eliminated, but immune complexes are not formed to stimulate naive B cells through Fc receptors. Memory B-cell responses are, however, not inhibited by antibody, so the Rh– mothers at risk must be identified and treated before a primary response has occurred. Because of their high affinity for antigen and alterations in their B-cell receptor signaling requirements, memory B cells are much more sensitive to the small amounts of antigen that cannot be efficiently cleared by the passive anti-Rh antibody. The ability of memory B cells to be activated to produce antibody, even when exposed to preexisting antibody, also allows secondary antibody responses to occur in individuals who are already immune.


Immunology_Janeway

Immunology_Janeway. These suppressive mechanisms might also explain a phenomenon called original antigenic sin. This term was coined to describe the tendency of people to make antibodies only against the epitopes expressed on the first influenza virus variant to which they are exposed, even in subsequent infections with viral variants that have additional, highly immunogenic epitopes (Fig. 11.34). Antibodies against the original virus will tend to suppress responses of naive B cells specific for the new epitopes. This might benefit the host by using only those B cells that can respond most rapidly and effectively to the virus. This pattern is broken only if the person is exposed to an influenza virus that lacks all epitopes seen in the original infection, because now no preexisting antibodies bind the virus, and naive B cells are able to respond.


Immunology_Janeway

Immunology_Janeway. A similar suppression of naive T-cell responses by antigen-specific memory T cells can occur in the setting of infection by lymphocytic choriomeningitis 1000 100 10 A B C D E F G Response to epitope Response to epitope Response to epitope A B C D E F A B C D Percentagenormal response 1000 100 10 Percentagenormal response 1000 100 10 Percentagenormal response Same individual at 20 years infected with a new variant in˜uenza virus makes antibody only against epitopes shared with original virus, not against epitopes shared with the variant encountered at age 5 years Same individual at 5 years infected with a variant in˜uenza virus makes antibody only against the epitopes shared with the original virus Individual at 2 years infected with in˜uenza virus makes antibody against all epitopes present on the virus


Immunology_Janeway

Immunology_Janeway. Fig. 11.34 When individuals who have been infected with one influenza virus responds preferentially to those epitopes shared variant of influenza virus are infected with a second or third with the original virus, and makes a smaller than normal response variant, they make antibodies only against epitopes that were to new epitopes on the virus (center panel). Even at age 20 years, present on the initial virus. A child infected for the first time with this commitment to respond to epitopes shared with the original an influenza virus at 2 years of age makes a response to all epitopes virus, and the subnormal response to new epitopes, is retained (right (left panel). At age 5 years, the same child exposed to a different panel). This phenomenon is called ‘original antigenic sin.’ virus (LCMV) in the mouse or dengue virus in humans. Mice that were primed with one strain of LCMV responded to a subsequent infection with a second strain of LCMV by expanding CD8 T cells that reacted to antigens


Immunology_Janeway

Immunology_Janeway. the mouse or dengue virus in humans. Mice that were primed with one strain of LCMV responded to a subsequent infection with a second strain of LCMV by expanding CD8 T cells that reacted to antigens specific for the first strain. However, this type of effect was not observed when responses to variable ovalbumin antigenic epitopes were examined in the setting of recurrent infections using the bacterial pathogen Listeria monocytogenes, suggesting that the suppression caused by ‘original antigenic sin’ does not occur in all immune responses.


Immunology_Janeway

Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Protective immunity against reinfection is one of the most important consequences of adaptive immunity, and results from the establishment of populations of long-lived memory B cells and memory T cells. These antigen-specific memory cells arise from the populations of lymphocytes that expand dramatically during the primary infection, and that survive at higher frequencies than in the naive lymphocyte repertoires. Both their increased frequency and their capacity to respond more rapidly to restimulation to the same antigen contribute to protective immunity, which can be transferred to naive recipients by memory B and T cells. Memory lymphocytes are maintained by their expression of receptors for cytokines, such as IL-7 and IL-15, that provide survival signals. Memory B cells can be distinguished by changes in their immunoglobulin genes because of isotype switching and somatic hypermutation, and secondary and subsequent immune responses are characterized by antibodies with increasing


Immunology_Janeway

Immunology_Janeway. by changes in their immunoglobulin genes because of isotype switching and somatic hypermutation, and secondary and subsequent immune responses are characterized by antibodies with increasing affinity for the antigen. The advent of receptor-specific reagents—MHC tetramers—has allowed for the direct analysis of the expansion and differentiation of effector and memory T cells. We now recognize that T-cell memory is complex, and memory T cells are quite heterogeneous, having central memory, effector memory, and tissue-resident memory subtypes. While CD8 T cells can generate effective primary responses in the absence of help from CD4 T cells, it is becoming clear that CD4 T cells have an integral role in regulating CD8 T-cell memory. These issues will be critical in understanding, for example, how to design effective vaccines for diseases such as HIV/AIDS.


Immunology_Janeway

Summary to Chapter 11.

Immunology_Janeway. Summary to Chapter 11.


Immunology_Janeway

Immunology_Janeway. Vertebrates resist infection by pathogenic microorganisms in several ways. The innate defenses can act immediately and may succeed in repelling the infection, but if not, they are followed by a series of induced early responses that help to contain the infection as adaptive immunity develops. These first two phases of the immune response rely on recognizing the presence of infection by using the nonclonotypic receptors of the innate immune system. They are summarized in Fig. 11.35 and covered in detail in Chapter 3. Several specialized subsets of immune cells, which can be viewed as intermediates between innate and adaptive immunity, act next and include the innate lymphoid cells, or ILCs, which are rapid responders to cytokines produced by innate sensor cells and can help to bias the CD4 T-cell response toward parallel subsets of effector T cells; and NK cells, which can be recruited to lymph nodes and secrete IFN-γ, and thus promote a TH1 response. The third phase of an immune


Immunology_Janeway

Immunology_Janeway. CD4 T-cell response toward parallel subsets of effector T cells; and NK cells, which can be recruited to lymph nodes and secrete IFN-γ, and thus promote a TH1 response. The third phase of an immune response is the adaptive immune response (see Fig. 11.35), which is mounted in the peripheral lymphoid tissue that serves the particular site of infection and takes several days to develop, because T and B lymphocytes must encounter their specific antigen, proliferate, and differentiate into effector cells. T-cell dependent B-cell responses cannot be initiated until antigen-specific TFH cells have had a chance to proliferate and differentiate. Once an adaptive immune response has occurred, the antibodies and effector T cells are dispersed via the circulation and recruited into the infected tissues; the infection is usually controlled and the pathogen is contained or eliminated. The final effector mechanisms used to clear an infection depend on the type of infectious agent, and in most cases


Immunology_Janeway

Immunology_Janeway. the infection is usually controlled and the pathogen is contained or eliminated. The final effector mechanisms used to clear an infection depend on the type of infectious agent, and in most cases they are the same as those employed in the early phases of immune defense; only the recognition mechanism changes and is now more selective (see Fig. 11.35).


Immunology_Janeway

Immunology_Janeway. Fig. 11.35 The components of the three phases of the immune response against different classes of microorganisms. The mechanisms of innate immunity that operate in the first two phases of the immune response are described in Chapters 2 and 3, and thymus-independent (T-independent) B-cell responses are covered in Chapter 10. The early phases contribute to the initiation of adaptive immunity, and they influence the functional character of the antigen-specific effector T cells and antibodies that appear on the scene in the late phase of the response. There are striking similarities in the effector mechanisms at each phase of the response; the main change is in the recognition structure used.


Immunology_Janeway

Immunology_Janeway. An effective adaptive immune response leads to a state of protective immunity. This state consists of the presence of effector cells and molecules produced in the initial response, and of immunological memory. Immunological memory is manifested as a heightened ability to respond to pathogens that have previously been encountered and successfully eliminated. Memory T and B lymphocytes have the property of being able to transfer immune memory to naive recipients. The mechanisms that maintain immunological memory include certain cytokines, such as IL-7 and IL-15, as well as homeostatic interactions between the T-cell receptors on memory cells with self peptide:self MHC complexes. The artificial induction of protective immunity, which includes immunological memory, by vaccination is the most outstanding accomplishment of immunology in the field of medicine. The understanding of how this is accomplished is now catching up with its practical success. However, as we will see in Chapter 13,


Immunology_Janeway

Immunology_Janeway. outstanding accomplishment of immunology in the field of medicine. The understanding of how this is accomplished is now catching up with its practical success. However, as we will see in Chapter 13, many pathogens do not induce protective immunity that completely eliminates the pathogen, so we will need to learn what prevents this before we can prepare effective vaccines against these pathogens.


Immunology_Janeway

Immunology_Janeway. Questions. 11.1 True or False: The immune response is a dynamic process that initiates with an antigen-independent response, which becomes more focused and powerful as it develops antigen specificity. Once the adaptive immune system develops, a single type of response is capable of eliminating any type of pathogen. 11.2 Multiple Choice: Which statement is incorrect? A. IL-12 and IL-18 production by macrophages and dendritic cells induces IFN-γ secretion by ILC1 to induce heightened killing of intracellular pathogens. B. ILC3s are activated by thymic stromal lymphopoietin (TSLP), which activates STAT5 and induces IL-17 production. C. Molecular patterns common to helminths activate IL-33 and IL-25 production, which in turn activates ILC2s to induce mucus production by goblet cells and mucosal smooth muscle contraction. D. ILC3-derived IL-22 acts on epithelial cells to induce production of antimicrobial peptides and promotes an enhanced barrier integrity.


Immunology_Janeway

Immunology_Janeway. D. ILC3-derived IL-22 acts on epithelial cells to induce production of antimicrobial peptides and promotes an enhanced barrier integrity. 11.3 Matching: Match the following proteins with their effect on T-cell migration. A. CXCR5 _______ i. Interacts with Pand E-selectin, expressed at activated endothelial cells B. PSGL-1 _______ ii. CXCL13 binding attracts TFH cells to the B-cell follicle C. FucT-VII _______ iii. Interacts with VCAM-1 to initiate extravasation of the effector T cells


Immunology_Janeway

Immunology_Janeway. B. PSGL-1 _______ ii. CXCL13 binding attracts TFH cells to the B-cell follicle C. FucT-VII _______ iii. Interacts with VCAM-1 to initiate extravasation of the effector T cells D. VLA-4 _______ iv. Necessary for the production of Pand E-selectin 11.4 Fill-in-the-Blanks: Expression of selective adhesion molecules among effector T cells helps compartmentalize their distribution. For example, T cells that are primed in the GALT induce the expression of the __________ integrin, which binds to ___________, which is constitutively expressed by the gut mucosal endothelial cells. These T cells also express the chemokine receptor ______, which attracts T cells to the lamina propria subjacent to the small intestine epithelium via a _________ gradient. This compartmentalization capacity is not unique to the gut and can be observed in other organs such as the skin. For example, expression of a glycosylated form of PSGL-1, ______, binds ________ on cutaneous vascular endothelium.


Immunology_Janeway

Immunology_Janeway. 11.5 Multiple Choice: Which of the following statements incorrectly describes TH1 macrophage activation? A. CD40 ligand sensitizes the macrophage to respond to IFN-γ B. LT-α can substitute for CD40 ligand in macrophage activation C. TNFR-I activation is antagonized by activated TH1 cells D. Macrophages are sensitized to IFN-γ by small amounts of bacterial LPS 11.6 Short Answer: How do M2 macrophages stimulate collagen production in order to promote tissue repair? 11.7 Multiple Choice: Which of the following is not true concerning type 3 responses? A. The primary innate effector cells are neutrophils, which are recruited by CXCL8 and CXCL2 and have an increased output due to G-CSF and GM-CSF B. At homeostasis, TH17 cells are present almost exclusively in the intestinal mucosa C. IL-17 is the central cytokine D. IL-22 is produced to induce antimicrobial peptide production and epithelial cell proliferation and shedding of natural killer cells


Immunology_Janeway

Immunology_Janeway. C. IL-17 is the central cytokine D. IL-22 is produced to induce antimicrobial peptide production and epithelial cell proliferation and shedding of natural killer cells E. IL-23 initiates the commitment of naive CD4+ T cells to the TH17 fate 11.8 Multiple Choice: Which of the following pathogens is able to induce a robust CD8+ T-cell response independent of CD4+ T-cell help? A. Streptococcus pneumoniae B. Lymphocytic choriomeningitis virus (LCMV) C. Listeria monocytogenes D. Staphylococcus aureus E. Salmonella


Immunology_Janeway

Immunology_Janeway. A. Streptococcus pneumoniae B. Lymphocytic choriomeningitis virus (LCMV) C. Listeria monocytogenes D. Staphylococcus aureus E. Salmonella F. Toxoplasma 11.9 Fill-in-the-Blanks: During an immune response to a pathogen, activated T cells express ______, a high-affinity IL-2 receptor component, and lose expression of ________, an IL-7 receptor component. The activated cells also generate different isoforms of _________, a protein tyrosine phosphatase expressed by all hematopoietic cells. Effector and central memory cells develop, and these can be distinguished by high expression of ___________________ in the former and ________ in the latter. The survival of both CD4+ and CD8+ memory T cells is dependent on _________, although the survival of CD8+ memory T cells is additionally dependent on _________. Section references. 11-1 The course of an infection can be divided into several distinct phases.


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Immunology_Janeway. Section references. 11-1 The course of an infection can be divided into several distinct phases. Mandell, G., Bennett, J., and Dolin, R. (eds): Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill Livingstone, 2000. Zhang, S.Y., Jouanguy, E., Sancho-Shimizu, V., von Bernuth, H., Yang, K., Abel, L., Picard, C., Puel, A., and Casanova, J.L.: Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol. Rev. 2007, 220:225–236. 11-2 The effector mechanisms that are recruited to clear an infection depend on the infectious agent. Bernink, J., Mjösberg, J., and Spits, H.: Th1and Th2-like subsets of innate lymphoid cells. Immunol. Rev. 2013, 252:133–138. Fearon, D.T., and Locksley, R.M.: The instructive role of innate immunity in the acquired immune response. Science 1996, 272:50–53. Gasteiger, G., and Rudensky, A.Y.: Interactions between innate and adaptive lymphocytes. Nat. Rev. Immunol. 2014, 14:631–639.


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Immunology_Janeway. Gasteiger, G., and Rudensky, A.Y.: Interactions between innate and adaptive lymphocytes. Nat. Rev. Immunol. 2014, 14:631–639. Janeway, C.A., Jr: The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 1992, 13:11–16. McKenzie, A.N.J., Spits, H., and Eberl, G.: Innate lymphoid cells in inflammation and immunity. Immunity 2014, 41:366–374. Neill, D.R., Wong, S.H., Bellosi, A., Flynn, R.J., Daly, M., Langford, T.K., Bucks, C., Kane, C.M., Fallon, P.G., Pannell, R., et al.: Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010, 464:1367–1370. Oliphant, C.J., Hwang, Y.Y., Walker, J.A., Salimi, M., Wong, S.H., Brewer, J.M., Englezakis, A., Barlow, J.L., Hams, E., Scanlon, S.T., et al.: MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 2014, 41:283–295.


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Immunology_Janeway. 11.10 True or False: CD27 is a marker of naive B cells as well as memory T cells. 11.11 Short Answer: How is inflammasome activation able to help induce type 1 and type 3 responses while blunting type 2 responses? 11.12 Matching: Match the cytokine to the downstream STAT. Walker, J.A., Barlow, J.L., and McKenzie, A.N.J.: Innate lymphoid cells—how did we miss them? Nat. Rev. Immunol. 2013, 13:75–87. 11-3 Effector T cells are guided to specific tissues and sites of infection by changes in their expression of adhesion molecules and chemokine receptors. Griffith, J.W., Sokol, C.L., and Luster, A.D.: Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 2014, 32:659–702. Hidalgo, A., Peired, A.J., Wild, M.K., Vestweber, D., and Frenette, P.S.: Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity 2007, 26:477–489.


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Immunology_Janeway. MacKay, C.R., Marston, W., and Dudler, L.: Altered patterns of T-cell migration through lymph nodes and skin following antigen challenge. Eur. J. Immunol. 1992, 22:2205–2210. Mantovani, A., Bonecchi, R., and Locati, M.: Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat. Rev. Immunol. 2006, 6:907–918. Mueller, S.N., Gebhardt, T., Carbone, F.R., and Heath, W.R.: Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 2013, 31:137–161. Sallusto, F., Kremmer, E., Palermo, B., Hoy, A., Ponath, P., Qin, S., Forster, R., Lipp, M., and Lanzavecchia, A.: Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur. J. Immunol. 1999, 29:2037–2045. 11-4 Pathogen-specific effector T cells are enriched at sites of infection as adaptive immunity progresses.


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Immunology_Janeway. 11-4 Pathogen-specific effector T cells are enriched at sites of infection as adaptive immunity progresses. Jenkins, M.K., Khoruts, A., Ingulli, E., Mueller, D.L., McSorley, S.J., Reinhardt, R.L., Itano, A., and Pape, K.A.: In vivo activation of antigen-specific CD4 T cells. Annu. Rev. Immunol. 2001, 19:23–45. 11-5 TH1 cells coordinate and amplify the host response to intracellular pathogens through classical activation of macrophages. Bekker, L.G., Freeman, S., Murray, P.J., Ryffel, B., and Kaplan, G.: TNF-α controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways. J. Immunol. 2001, 166:6728–6734. Ehlers, S., Kutsch, S., Ehlers, E.M., Benini, J., and Pfeffer, K.: Lethal granuloma disintegration in mycobacteria-infected TNFRp55–/– mice is dependent on T cells and IL-12. J. Immunol. 2000, 165:483–492.


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Immunology_Janeway. Hsieh, C.S., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O’Garra, A., and Murphy, K.M.: Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 1993, 260:547–549. Muñoz-Fernández, M.A., Fernández, M.A., and Fresno, M.: Synergism between tumor necrosis factor-α and interferon-γ on macrophage activation for the killing of intracellular Trypanosoma cruzi through a nitric oxide-dependent mechanism. Eur. J. Immunol. 1992, 22:301–307. Murray, P.J., and Wynn, T.A.: Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011, 11:723–737. Stout, R.D., Suttles, J., Xu, J., Grewal, I.S., and Flavell, R.A.: Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J. Immunol. 1996, 156:8–11. 11-6 Activation of macrophages by TH1 cells must be tightly regulated to avoid tissue damage. Duffield, J.S.: The inflammatory macrophage: a story of Jekyll and Hyde. Clin. Sci. 2003, 104:27–38.


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Immunology_Janeway. 11-6 Activation of macrophages by TH1 cells must be tightly regulated to avoid tissue damage. Duffield, J.S.: The inflammatory macrophage: a story of Jekyll and Hyde. Clin. Sci. 2003, 104:27–38. Labow, R.S., Meek, E., and Santerre, J.P.: Model systems to assess the destructive potential of human neutrophils and monocyte-derived macrophages during the acute and chronic phases of inflammation. J. Biomed. Mater. Res. 2001, 54:189–197. Wigginton, J.E., and Kirschner, D.: A model to predict cell-mediated immune regulatory mechanisms during human infection with Mycobacterium tuberculosis. J. Immunol. 2001, 166:1951–1967. 11-7 Chronic activation of macrophages by TH1 cells mediates the formation of granulomas to contain intracellular pathogens that cannot be cleared. James, D.G.: A clinicopathological classification of granulomatous disorders. Postgrad. Med. J. 2000, 76:457–465. 11-8 Defects in type 1 immunity reveal its important role in the elimination of intracellular pathogens.


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Immunology_Janeway. 11-8 Defects in type 1 immunity reveal its important role in the elimination of intracellular pathogens. Berberich, C., Ramirez-Pineda, J.R., Hambrecht, C., Alber, G., Skeiky, Y.A., and Moll, H.: Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens. J. Immunol. 2003, 170:3171–3179. Biedermann,T., Zimmermann, S., Himmelrich, H., Gumy,A., Egeter, O., Sakrauski, A.K., Seegmuller, I., Voigt, H., Launois, P., Levine, A.D., et al.: IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat. Immunol. 2001, 2:1054–1060. Neighbors, M., Xu, X., Barrat, F.J., Ruuls, S.R., Churakova, T., Debets, R., Bazan, J.F., Kastelein, R.A., Abrams, J.S., and O’Garra, A.: A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on interferon gamma production. J. Exp. Med. 2001, 194:343–354.


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Immunology_Janeway. 11-9 TH2 cells coordinate type 2 responses to expel intestinal helminths and repair tissue injury. Artis, D., and Grencis, R.K.: The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol. 2008, 1:252–264. Fallon, P.G., Ballantyne, S.J., Mangan, N.E., Barlow, J.L., Dasvarma, A., Hewett, D.R., McIlgorm, A., Jolin, H.E., and McKenzie, A.N.J.: Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 2006, 203:1105–1116. Finkelman, F.D., Shea-Donohue, T., Goldhill, J., Sullivan, C.A., Morris, S.C., Madden, K.B., Gauser, W.C., and Urban, J.F., Jr: Cytokine regulation of host defense against parasitic intestinal nematodes. Annu. Rev. Immunol. 1997, 15:505–533. Humphreys, N.E., Xu, D., Hepworth, M.R., Liew, F.Y., and Grencis, R.K.: IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 2008, 180:2443–2449.


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Immunology_Janeway. Humphreys, N.E., Xu, D., Hepworth, M.R., Liew, F.Y., and Grencis, R.K.: IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 2008, 180:2443–2449. Liang, H.-E., Reinhardt, R.L., Bando, J.K., Sullivan, B.M., Ho, I.-C., and Locksley, R.M.: Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 2012, 13:58–66. Maizels, R.M., Pearce, E.J., Artis, D., Yazdanbakhsh, M., and Wynn, T.A.: Regulation of pathogenesis and immunity in helminth infections. J. Exp. Med. 2009, 206:2059–2066. Ohnmacht, C., Schwartz, C., Panzer, M., Schiedewitz, I., Naumann, R., and Voehringer, D.: Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010, 33:364–374. Saenz, S.A., Noti, M., and Artis, D.: Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 2010, 31:407–413.


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Immunology_Janeway. Saenz, S.A., Noti, M., and Artis, D.: Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 2010, 31:407–413. Sullivan, B.M., and Locksley, R.M.: Basophils: a nonredundant contributor to host immunity. Immunity 2009, 30:12–20. Van Dyken, S.J., and Locksley, R.M.: Interleukin-4and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 2013, 31:317–343. 11-10 TH17 cells coordinate type 3 responses to enhance the clearance of extracellular bacteria and fungi. Aujla, S.J., Chan, Y.R., Zheng, M., Fei, M., Askew, D.J., Pociask, D.A., Reinhart, T.A., Mcallister, F., Edeal, J., Gaus, K., et al.: IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat. Med. 2008, 14:275–281.


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Immunology_Janeway. Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait-Yahia, S., Maat, C., Pin, J.J., Garrone, P., Garcia, E., Saeland, S., et al.: T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 1996, 183:2593–2603. Happel, K.I., Zheng, M., Young, E., Quinton, L.J., Lockhart, E., Ramsay, A.J., Shellito, J.E., Schurr, J.R., Bagby, G.J., Nelson, S., et al.: Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 2003, 170:4432–4436. LeibundGut-Landmann, S., Gross, O., Robinson, M.J., Osorio, F., Slack, E.C., Tsoni, S.V., Schweighoffer, E., Tybulewicz, V., Brown, G.D., Ruland, J., et al.: Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 2007, 8:630–638.


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Immunology_Janeway. Ouyang, W., Kolls, J.K., and Zheng, Y.: The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008, 28:454–467. Romani, L.: Immunity to fungal infections. Nat. Rev. Immunol. 2011, 11:275–288. Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A., and Artis, D.: CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011, 34:122–134. Zheng, Y., Valdez, P.A., Danilenko, D.M., Hu, Y., Sa, S.M., Gong, Q., Abbas, A.R., Modrusan, Z., Ghilardi, N., De Sauvage, F.J., et al.: Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 2008, 14:282–289. 11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions.


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Immunology_Janeway. 11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions. Cua, D.J., Sherlock, J., Chen, Y., Murphy, C.A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., et al.: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421:744–748. Ghilardi, N., Kljavin, N., Chen, Q., Lucas, S., Gurney, A.L., and De Sauvage, F.J.: Compromised humoral and delayed-type hypersensitivity responses in IL-23deficient mice. J. Immunol. 2004, 172:2827–2833. Park, A.Y., Hondowics, B.D., and Scott, P.: IL-12 is required to maintain a Th1 response during Leishmania major infection. J. Immunol. 2000, 165:896–902. Yap, G., Pesin, M., and Sher, A.: Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen Toxoplasma gondii. J. Immunol. 2000, 165:628–631.


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Immunology_Janeway. 11-12 Effector T cells can be activated to release cytokines independently of antigen recognition. Guo, L., Junttila, I.S., and Paul, W.E.: Cytokine-induced cytokine production by conventional and innate lymphoid cells. Trends Immunol. 2012, 33:598–606. Kohno, K., Kataoka, J., Ohtsuki, T., Suemoto, Y., Okamoto, I., Usui, M., Ikeda, M., and Kurimoto, M.: IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 1997, 158:1541–1550. 11-13 Effector T cells demonstrate plasticity and cooperativity that enable adaptation during anti-pathogen responses. Basu, R., Hatton, R.D., and Weaver, C.T.: The Th17 family: flexibility follows function. Immunol. Rev. 2013, 252:89–103.


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