Immunology_Janeway

Immunology_Janeway. Effector T cells augment the effector functions of innate immune cells. Immunological memory. Fig. 11.1 The course of a typical acute infection that is cleared by an adaptive immune response. 1. The infectious agent colonizes and its numbers increase as it replicates. The innate response is initiated immediately following detection of the pathogen. 2. When numbers of the pathogen exceed the threshold dose of antigen required for an adaptive response, the response is initiated; the pathogen continues to grow, restrained by responses of the innate immune system. At this stage, immunological memory also starts to be induced. 3. After 4–7 days, effector cells and molecules of the adaptive response start to clear the infection. 4. When the infection has been cleared and the dose of antigen has fallen below the response threshold, the response ceases, but antibody, residual effector cells, and immunological memory provide lasting protection against reinfection in most cases.


Immunology_Janeway

Immunology_Janeway. During this period, specific immunological memory is also established by adaptive immune cells. This ensures a rapid reinduction of antigen-specific antibody and effector T cells on encounter with the same pathogen during a secondary immune response, thus providing long-lasting and often lifelong protection against the pathogen. Immunological memory is discussed in the last part of the chapter. Memory responses differ in several ways from primary responses. We discuss the reasons for this, and what is known about how immunological memory is maintained. Integration of innate and adaptive immunity in response to specific types of pathogens.


Immunology_Janeway

Immunology_Janeway. The immune response is a dynamic process, and both its nature and its intensity change over time. It begins with the antigen-independent responses of innate immunity and becomes both more focused on the pathogen and more powerful as the antigen-specific adaptive immune response matures. The character of the response differs contingent on the type of pathogen. Different types of pathogens (for example, intracellular and extracellular bacteria, viruses, helminthic parasites, and fungi) elicit different types of immune response (for example, type 1, 2, or 3), so that the most effective immune response is induced for effective elimination of the pathogen. The innate immune system not only anticipates and initiates the adaptive Tand B-cell responses, but continues to provide effector cells and reinforcing pathways of the different types of immunity throughout infection. Early in the response, different subsets of innate lymphoid cells (ILCs) are activated by cytokines produced by innate


Immunology_Janeway

Immunology_Janeway. reinforcing pathways of the different types of immunity throughout infection. Early in the response, different subsets of innate lymphoid cells (ILCs) are activated by cytokines produced by innate sensor cells. This early response acts to constrain pathogen entry at the initial site of infection to prevent dissemination while the adaptive response develops. However, the more sensitive and specific actions of effector T cells and class-switched, affinity-matured antibodies are often required for the complete elimination of infection, or sterilizing immunity. In this part of the chapter, we provide an overview of how the different phases of an immune response are orchestrated in space and time and then discuss how distinct cytokines from innate sensor cells activate different innate lymphoid cell subsets to restrain pathogen invasion and direct pathogen-specific defenses while the adaptive response is developing.


Immunology_Janeway

Immunology_Janeway. 11-1 The course of an infection can be divided into several distinct phases. Although some of the microbe-associated molecular patterns (MAMPs) of different types of pathogens are shared, others are not, and these differences underlie the induction of distinct patterns of innate and adaptive immunity that can be broadly grouped into type 1, type 2, and type 3 responses, as will be discussed below. Irrespective of the inciting pathogen and the pattern of immune response it provokes, however, the tempo of the host response is similar and can be broken down into various stages (Fig. 11.1, and see Fig. 3.38).


Immunology_Janeway

Immunology_Janeway. In the first stage of infection, a new host is exposed to infectious particles either shed by an infected individual or present in the environment. The numbers, route, mode of transmission, and stability of an infectious agent outside the host determine its infectivity. The first contact with a new host occurs through an epithelial surface, such as the skin or the mucosal surfaces of the respiratory, gastrointestinal, or urogenital tracts. After making contact, an infectious agent must establish a focus of infection. It must either adhere to the epithelial surface and colonize it, or penetrate it to replicate in the tissues (Fig. 11.2). Bites by arthropods (insects and ticks) and wounds breach the epidermal barrier and help some microorganisms gain entry through the skin. Integration of innate and adaptive immunity in response to specific types of pathogens.


Immunology_Janeway

Immunology_Janeway. Integration of innate and adaptive immunity in response to specific types of pathogens. Fig. 11.2 Infections and the responses to them can be divided antigen and antigen-loaded dendritic cells to lymphatics (second into a series of stages. These are illustrated here for a pathogenic panel) and thence to local lymph nodes (third panel). This leads to microorganism (red) entering across a wound in an epithelium. The an adaptive immune response in the lymph node that involves the microorganism first adheres to epithelial cells and then invades activation and further differentiation of B cells and T cells with the beyond the epithelium into underlying tissues (first panel). A local eventual production of antibody and effector T cells, which clear the innate immune response helps to contain the infection, and delivers infection (fourth panel).


Immunology_Janeway

Immunology_Janeway. Only when a microorganism has successfully established a focus of infection in the host does disease occur (see Fig. 11.2). With few exceptions, little damage will be caused unless the pathogen spreads from the original focus or secretes toxins that spread to other parts of the body. Extracellular pathogens spread by direct extension of the infection through the lymphatics or the bloodstream. Spread into the bloodstream usually occurs only after the lymphatic system has been overwhelmed. Obligate intracellular pathogens spread from cell to cell; they do so either by direct transmission from one cell to the next or by release into the extracellular fluid and reinfection of both adjacent and distant cells. Facultative intracellular pathogens can do the same after a period of survival in the extracellular environment. In contrast, some of the bacteria that cause gastroenteritis exert their effects without spreading into the tissues. They establish a site of infection on the luminal


Immunology_Janeway

Immunology_Janeway. the extracellular environment. In contrast, some of the bacteria that cause gastroenteritis exert their effects without spreading into the tissues. They establish a site of infection on the luminal surface of the epithelium lining the gut and cause pathology by damaging the epithelium or by secreting toxins that cause damage either in situ or after crossing the epithelial barrier and entering the circulation.


Immunology_Janeway

Immunology_Janeway. The establishment of a focus of infection in tissues and the response of the innate immune system produce changes in the immediate environment. Many microorganisms are repelled or kept in check at this stage by innate defenses, which are triggered by stimulation of the various germlineencoded pattern recognition receptors expressed by innate sensor cells—such as epithelial cells, tissue-resident mast cells, macrophages, and dendritic cells (see Chapters 2 and 3). Cytokines and chemokines produced by pathogen-activated innate sensor cells initiate local inflammation, and also activate ILCs. These responses are activated within minutes to hours, and are sustained for at least several days. The inflammatory response is induced through activation of the endothelium of local post-capillary venules (see Fig. 3.31). This leads to the recruitment of circulating innate effector cells, particularly neutrophils and monocytes, thereby increasing the numbers of phagocytes available for microbe


Immunology_Janeway

Immunology_Janeway. venules (see Fig. 3.31). This leads to the recruitment of circulating innate effector cells, particularly neutrophils and monocytes, thereby increasing the numbers of phagocytes available for microbe clearance. As monocytes enter tissue and become activated, additional inflammatory cells are attracted into the infected tissue so that the inflammatory response is maintained and reinforced. Leakiness of the inflamed endothelium also leads to the influx of serum proteins, including complement, activation of which in a primary infection occurs mainly via the alternative and lectin pathways (see Fig. 2.15). This results in the production of the anaphylatoxins C3a and C5a, which further activate the vascular endothelium; and C3b, which opsonizes microbes for more effective clearance by recruited phagocytes. This early phase of the inflammatory response is largely nonspecific for the type of pathogen.


Immunology_Janeway

Immunology_Janeway. Concordant with the production of pro-inflammatory cytokines such as TNF-α, which activate nonspecific inflammation, innate sensor cells produce additional cytokines that differentially activate specific subsets of ILCs within the first hours of an infection. This is due to the expression of unique MAMPs—or unique combinations of MAMPs—by different types of pathogens, which elicit different patterns of cytokines from innate sensor cells. This has important consequences in directing the type of immune response that will be mounted against the pathogen, as subsets of ILCs are differentially activated to produce their own effector cytokines and chemokines contingent on the pattern of cytokines produced by innate sensor cells (Fig. 11.3). The products of activated ILCs amplify and coordinate local innate responses that are better tailored to resist specific types of pathogens, and also alter the recruitment and maturation of different myelomonocytic innate effector cells (that is,


Immunology_Janeway

Immunology_Janeway. local innate responses that are better tailored to resist specific types of pathogens, and also alter the recruitment and maturation of different myelomonocytic innate effector cells (that is, granulocytes like neutrophils, eosinophils, and basophils, or monocytes) at the site of infection. Cytokines produced by ILCs may also guide the development of naive T cells into distinct effector subsets (for example, TH1, TH2, or TH17 cells)—either directly by acting on naive T cells themselves or indirectly by modulating the activation of dendritic cells that migrate to regional lymphoid tissues to prime naive T cells. In this way, ILCs perform an important bridging function during the first few days of an immune response, by both providing for innate defense and influencing the type of adaptive response that follows.


Immunology_Janeway

Immunology_Janeway. Adaptive immunity is triggered when an infection eludes or overwhelms the innate defense mechanisms and generates a threshold level of antigen (see Fig. 11.1). Adaptive immune responses are then initiated in the local lymphoid Normal mice and humans Mice and humans lacking innate immunity (PMN– , MAC–) SCID or RAG-defcient mice and humans (PMN+ , MAC+ , T/B–)


Immunology_Janeway

Immunology_Janeway. Integration of innate and adaptive immunity in response to specific types of pathogens. 449 tissue, in response to antigens presented by dendritic cells activated during the course of the innate immune response (see Fig. 11.2, second and third panels). Antigen-specific effector T cells and antibody-secreting B cells are generated by clonal expansion and differentiation over several days, during which innate responses orchestrated by ILCs ‘buy time’ for the adaptive response to mature. Within several days of infection, antigen-specific T cells and then antibodies are released into the blood, and from there can enter the site of infection (see Fig. 11.2, fourth panel). Adaptive responses are more powerful because antigen-specific targeting of innate effector mechanisms can eliminate pathogens more precisely. For example, antibodies can activate complement to directly kill pathogens; they can opsonize pathogens for enhanced phagocytosis; and they can arm Fc-bearing innate effector cells


Immunology_Janeway

Immunology_Janeway. more precisely. For example, antibodies can activate complement to directly kill pathogens; they can opsonize pathogens for enhanced phagocytosis; and they can arm Fc-bearing innate effector cells for release of microbicidal factors or recruit the cytocidal actions of natural killer (NK) cells—these last capabilities known as antibody-dependent cell-mediated cytotoxicity (ADCC). Effector CD8 T cells can directly kill antigen-bearing target cells via similar cytocidal cytotoxic actions, and effector CD4 T cells can directly release cytokines onto macrophages to enhance their microbicidal actions.


Immunology_Janeway

Immunology_Janeway. Resolution of an infection typically involves complete clearance of the pathogen, and thus the source of antigens, over the course of days to weeks, following which most effector lymphocytes die—a stage known as clonal contraction (see Section 11-16). What remain are long-lived antibody-producing plasma cells that sustain circulating antibodies for months to years, and small numbers of memory B and T cells that may also persist for years, poised for an accelerated adaptive response in the event of future encounters with the same pathogen. Thus, in addition to clearing the infectious agent, an effective adaptive immune response prevents reinfection. For some infectious agents, this protection is essentially absolute, whereas for others infection is only reduced or attenuated on reexposure to the pathogen.


Immunology_Janeway

Immunology_Janeway. It is not known how many infections are dealt with solely by the nonadaptive mechanisms of innate immunity, because such infections are eliminated early and produce little in the way of symptoms or pathology. Innate immunity does, however, seem to be essential for effective host defense, as shown by the progression of infection in mice that lack components of innate immunity but have an intact adaptive immune system (Fig. 11.4). Conversely, many infections can be curbed—but not cleared—in the absence of adaptive immunity.


Immunology_Janeway

Immunology_Janeway. After many types of infection, little or no residual pathology follows an effective primary adaptive response. In some cases, however, the infection itself, or the response it induces, causes significant tissue damage. In yet other cases, such as infection with cytomegalovirus or Mycobacterium tuberculosis, the pathogen is contained but not eliminated, and can persist in a latent form. If the adaptive immune response is later weakened, as it is in acquired immune deficiency syndrome (AIDS), these pathogens may resurface to cause virulent systemic infections. We will focus on the strategies used by certain pathogens to evade or subvert adaptive immunity, and thereby establish a persistent, or chronic, infection, in Chapter 13. 11-2 The effector mechanisms that are recruited to clear an infection depend on the infectious agent.


Immunology_Janeway

Immunology_Janeway. 11-2 The effector mechanisms that are recruited to clear an infection depend on the infectious agent. Most infections ultimately engage both Tand B-cell-mediated adaptive immunity, and in many cases both are helpful in clearing or containing the pathogen and setting up protective immunity. However, the relative importance of the different effector mechanisms, and the effective classes of antibody involved, vary with different pathogens. An emerging concept is that there are different types of immune responses that are focused on the activation of distinct immune effector modules (see Section 1-19). In each type of immune response, a specific collection of innate and adaptive mechanisms act together Duration of infection


Immunology_Janeway

Immunology_Janeway. Duration of infection Fig. 11.4 The time course of infection in normal and immunodeficient mice and humans. The red curve shows the rapid growth of microorganisms in the absence of innate immunity, when macrophages (MAC) and polymorphonuclear leukocytes (PMN) are lacking. The green curve shows the course of infection in mice and humans that have innate immunity but have no T or B lymphocytes and so lack adaptive immunity. The yellow curve shows the normal course of an infection in immunocompetent mice or humans.


Immunology_Janeway

Immunology_Janeway. to eliminate a specific type of pathogen. Each effector module includes subsets of innate sensor cells, ILCs, effector T cells, and antibody isotypes, which coordinate with subsets of circulating or tissue-resident myelomonocytic cells whose microbicidal functions they recruit and enhance (Fig. 11.5). Circulating myelomonocytic cells are important innate effector cells that are targeted for heightened functions by ILCs, effector T cells, and antibodies following their recruitment into sites of infection. In their order of abundance in circulating blood, these include neutrophils, monocytes (which enter inflamed tissues and differentiate into activated macrophages), eosinophils, and basophils. Tissue-resident mast cells, which share many functions with basophils, are also targeted for heightened function.


Immunology_Janeway

Immunology_Janeway. It appears that each of the three major ILC and effector CD4 T-cell subsets (ILC1/ILC2/ILC3 and TH1/TH2/TH17, respectively) evolved to enhance and coordinate the functions of, and integrate adaptive immunity with, different arms of the myelomonocytic pathway for optimal eradication of different classes of pathogens: monocyte and macrophages are enhanced by TH1 cells; eosinophils, basophils, and mast cells by TH2 cells; and neutrophils by TH17 cells. The three major types of immune responses are controlled by cytokine and chemokine networks, as discussed below. Fig. 11.5 Integration of ILCs, T-cell subsets, and innate effector cells into immune effector modules. The major inductive and effector cytokines, and transcription factors (e.g., ID2, T-bet, GATA3, RORγt, and AHR), that are associated with each effector module are shown. See text for details.


Immunology_Janeway

Immunology_Janeway. Type 1 responses are characterized by the actions of group 1 ILCs (ILC1), TH1 cells, opsonizing IgG isotypes (for example, IgG1 and IgG2), and macrophages in response to intracellular pathogens, including intracellular bacteria, viruses, and parasites (see Fig. 11.5). Type 2 responses are characterized by the actions of group 2 ILCs (ILC2), TH2 cells, IgE, and the innate effector cells eosinophils, basophils, and tissue mast cells, the latter two of which are armed for function by IgE bound to surface Fcε receptors. Type 2 responses are induced by, and target, multicellular parasites, or helminths. Type 3 responses are characterized by the actions of group 3 ILCs (ILC3), TH17 cells, opsonizing IgG isotypes, and neutrophils in response to extracellular bacteria and fungi. It is the activation of different subsets of ILCs early in the innate response that sets the stage for polarized type 1, type 2, or type 3 responses. Unlike the effector CD4 T cells with which they share overlapping


Immunology_Janeway

Immunology_Janeway. of different subsets of ILCs early in the innate response that sets the stage for polarized type 1, type 2, or type 3 responses. Unlike the effector CD4 T cells with which they share overlapping functional features, ILCs do not require priming and differentiation in order to acquire their effector functions; hence they are able to respond rapidly to amplify the activities of resident and recruited innate effector cells. Here we will consider in more detail the induction and actions of ILC subsets, as these responses precede and are integrated with adaptive T-cell responses.


Immunology_Janeway

Immunology_Janeway. As discussed in Chapter 3, ILC1s and related NK cells are characterized by their production of IFN-γ in response to IL-12 and IL-18 produced by pathogen-activated dendritic cells and macrophages. Functionally, ILC1s and NK cells most closely resemble TH1 cells and CTLs, respectively. ILC1s lack the cytolytic granules that are characteristic of NK cells and CTLs, and appear to promote clearance of intracellular pathogens through their activation of infected macrophages by the release of IFN-γ. Thus, through their production of IL-12 and IL-18, macrophages can rapidly induce ILC1 production of IFN-γ, which acts back on the macrophage to induce its heightened killing of intracellular pathogens several days prior to the development and recruitment of TH1 cells. Moreover, the production of IFN-γ by ILC1s may contribute to the early polarization of TH1 cells, linking the effector function of these cells to the induction of the TH1 cell response that follows. Similarly, the rapid induction


Immunology_Janeway

Immunology_Janeway. by ILC1s may contribute to the early polarization of TH1 cells, linking the effector function of these cells to the induction of the TH1 cell response that follows. Similarly, the rapid induction of the cytolytic activity of NK cells enables the killing of a range of pathogen-infected cells, through the recognition of surface molecules that are expressed on the target cells (see Section 3-23), in advance of the antigen-driven development and deployment of cytolytic CD8 T cells. Also, similar to the effect on TH1 cells of IFN-γ production by ILC1s, the production of IFN-γ by activated NK cells may contribute to the enhanced differentiation of cytolytic CD8 T cells.


Immunology_Janeway

Immunology_Janeway. ILC2s that reside in mucosal tissues are preferentially activated by the cytokines thymic stromal lymphopoietin (TSLP), a STAT5-activating cytokine, and IL-33 or IL-25, each of which are produced in response to helminths. These cytokines are primarily produced by epithelial cells that sense molecular patterns common to helminths, such as chitin, a polysaccharide polymer of β-1,4-N-acetylglucosamine that is a widespread constituent of helminths, the exoskeletons of insects, and some fungi. Activated ILC2s rapidly produce large amounts of IL-13 and IL-5; IL-13 stimulates mucus production by goblet cells in the epithelium and mucosal smooth muscle contractions that facilitate worm expulsion; and IL-5 stimulates the production and activation of eosinophils that can kill worms. Unlike TH2 cells, with which they share functional features, ILC2s appear to produce little or no IL-4 in vivo, suggesting that they might not directly promote TH2 differentiation. However, eosinophils and basophils


Immunology_Janeway

Immunology_Janeway. with which they share functional features, ILC2s appear to produce little or no IL-4 in vivo, suggesting that they might not directly promote TH2 differentiation. However, eosinophils and basophils that are recruited by chemokines produced by ILC2s are activated to produce IL-4 in response to the IL-5 and IL-13 produced by ILC2s, possibly providing an indirect mechanism by which TH2 differentiation is directed by ILC2s. Moreover, IL-13 produced by ILC2s appears to regulate the activation and migration to regional lymphoid tissues of dendritic cells that promote TH2 differentiation, although it is unclear whether these dendritic cells can also produce IL-4.


Immunology_Janeway

Immunology_Janeway. ILC3s play a critical early role in defense against extracellular bacteria and fungi at barrier tissues. Similarly toTH17 cells, ILC3s are responsive to IL-23 and IL-1β; these cytokines elicit the production of IL-17 and IL-22, which promote early type 3 responses. IL-17 is a pro-inflammatory cytokine that acts on a variety of cells, including stromal cells, epithelial cells, and myeloid cells, to stimulate the production of other pro-inflammatory cytokines (for example, IL-6 and IL-1β), hematopoietic growth factors (G-CSF and GM-CSF), and chemokines that recruit neutrophils and monocytes. IL-22 acts on epithelial cells to induce their production of antimicrobial peptides (AMPs) and promote enhanced barrier integrity. As with other ILCs, the cytokines produced by ILC3s act indirectly via IL-6 and IL-1β in a positive feedback loop to enhance type 3 responses by increasing local production of IL-23 and IL-1β. Through induction of elevated IL-6, IL-1β, and IL-23, ILC3s may also promote


Immunology_Janeway

Immunology_Janeway. IL-6 and IL-1β in a positive feedback loop to enhance type 3 responses by increasing local production of IL-23 and IL-1β. Through induction of elevated IL-6, IL-1β, and IL-23, ILC3s may also promote the differentiation of TH17 cells in mucosal lymphoid tissues, where they can be found in substantial numbers.


Immunology_Janeway

Immunology_Janeway. In a further parallel with effector CD4 T cells, an important feature of ILCs is that they ‘license’ other innate immune cells for killing or expulsion of microbes, but they do not do so themselves. Instead, myelomonocytic cells, and even cells of the mucosal epithelium, are the agents of ILCs and effector CD4 T cells; they are recruited and/or activated through the pro-inflammatory cytokines and chemokines that these lymphoid cells produce. An exception is NK cells, which, like effector CD8 T cells, directly kill target cells that harbor intracellular pathogens. As we will discuss below, because of their ability to focus effector cytokines on antigen-bearing target cells and to induce B-cell maturation and the production of class-switched antibodies, effector CD4 T cells provide an additional layer of licensing of innate effector cells that increases their lethality and ability to achieve microbial clearance. Summary.


Immunology_Janeway

Immunology_Janeway. Summary. Integration of the innate and adaptive immune responses is required for effective protection of the host against pathogenic microorganisms. The responses of the innate immune system act early to restrain pathogens while simultaneously helping to initiate the adaptive immune response, which takes a longer time to fully develop. Different types of pathogens cause the activation of different patterns of cytokine production by innate sensor cells. This, in turn, promotes the activation of different patterns of innate lymphoid cells (ILCs), which recruit innate effector cells to sites of infection and contribute to the differentiation of parallel programs of CD4 T-cell differentiation. Coordination of the induction of different immune effector modules that are composed of related subsets of ILCs, innate effector cells, CD4 effector T cells, and class-switched antibodies underlies the different types of immunity directed against different types of pathogens.


Immunology_Janeway

Immunology_Janeway. Effector T cells augment the effector functions of innate immune cells.


Immunology_Janeway

Immunology_Janeway. In Chapter 9 we described how dendritic cells loaded with their antigen cargo migrate away from the infected tissue through the lymphatics to enter secondary lymphoid tissues, where they initiate the adaptive immune response. We discussed how CD8 T cells are primed to become cytotoxic effectors that are specialized for killing infected target cells that express MHC class I molecules. We also saw how transcription factor networks activated by specific cytokines direct the differentiation of naive CD4 T cells into distinct classes of CD4 effector T cells—TH1, TH2, and TH17 (see Fig. 9.31). In Chapter 10 we discussed the specialized role of TFH cells, which engage antigen-bearing B cells to control antibody class switching and B-cell maturation in germinal centers in the context of type 1, type 2, and type 3 responses. We now turn our attention to the specialized roles of subsets of effector CD4 T cells that emigrate from secondary lymphoid tissues after their differentiation to


Immunology_Janeway

Immunology_Janeway. 1, type 2, and type 3 responses. We now turn our attention to the specialized roles of subsets of effector CD4 T cells that emigrate from secondary lymphoid tissues after their differentiation to orchestrate the functions of innate immune cells at sites of infection.


Immunology_Janeway

Immunology_Janeway. As discussed in the preceding sections, the pattern of cytokines produced by the innate immune response during the early course of infection is determined by how the microorganism influences the behavior of innate sensor cells and the different subsets of ILCs they engage. The local inflammatory conditions produced by these interactions have a major impact on how T cells differentiate during their initial contact with dendritic cells, thus determining the subsets of effector T cells that are generated (see Chapter 9). In turn, the recruitment of effector T cells to sites of infection sustains and amplifies innate effector cell responses initiated by ILCs through effector mechanisms that require antigen-specific recognition, whether through cell–cell contact between CD4 or CD8 T cells and cell targets bearing their cognate antigens, or via pathogen-specific antibodies. In this part of the chapter, we will discuss how the differentiation of effector CD4 T cells generated during the


Immunology_Janeway

Immunology_Janeway. and cell targets bearing their cognate antigens, or via pathogen-specific antibodies. In this part of the chapter, we will discuss how the differentiation of effector CD4 T cells generated during the adaptive immune response alters their expression of surface receptors and causes them to leave secondary lymphoid tissues and home to sites of infection. We will then consider how TH1, TH2, and TH17 cells interact with innate immune cells at sites of infection to bring about the clearance of the specific pathogens that elicit their development and recruitment. Finally, we will consider how the primary effector response is terminated as the pathogen is eliminated.


Immunology_Janeway

Immunology_Janeway. 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.


Immunology_Janeway

Immunology_Janeway. When naive T cells differentiate into effector T cells, changes occur in the expression of specific surface molecules that redirect their trafficking from T-cell zones into B-cell zones, in the case of TFH cells, or from lymphoid to nonlymphoid tissues, in the case of other effector T cells. During the 3–5 days required for differentiation of naive T cells into effector T cells within secondary lymphoid tissues, marked changes occur in the expression of these trafficking molecules, including alterations in the display of selectins and their ligands, integrins, and chemokine receptors. As we will see, some of these changes are generic, and are common to all CD4 and CD8 effector T cells. Others are tissue-specific, facilitating the recruitment of T cells back to the tissues in which they were primed. Yet others are T-cell subset-specific, particularly the patterns of chemokine receptor expression, which are important in directing TFH cells to germinal centers, where they provide help to


Immunology_Janeway

Immunology_Janeway. primed. Yet others are T-cell subset-specific, particularly the patterns of chemokine receptor expression, which are important in directing TFH cells to germinal centers, where they provide help to developing B cells, or in directing TH1, TH2, and TH17 cells to the same tissue sites as the myelomonocytic cells whose effector functions they will recruit and enhance.


Immunology_Janeway

Immunology_Janeway. Naive CD4 T cells that are activated by antigen and become TFH cells acquire expression of CXCR5 and lose expression of CCR7 and S1PR1, the receptor for the chemotactic lipid sphingosine 1-phosphate (see Section 9-7). The constitutive expression of CXCL13 by follicular dendritic cells establishes a gradient that attracts developing TFH cells first to the border of the T-cell zone with a B-cell follicle, where they can interact with B cells that present their cognate antigen, and then into the B-cell follicle, where they provide help to germinal center B cells. Unlike TFH cells, other effector CD4 and CD8 T cells must leave the lymphoid tissue in which they have developed to interact with myelomonocytic cells at sites of infection in nonlymphoid tissues. The exit of effector T cells is induced by their loss of CCR7 and their reexpression of S1PR1. S1PR1 is normally rapidly downregulated by CD69 following antigenic stimulation


Immunology_Janeway

Immunology_Janeway. Fig. 11.6 Effector T cells change their surface molecules, allowing them to home to sites of infection. Naive T cells home to lymph nodes through the binding of L-selectin to sulfated carbohydrates displayed by various proteins, such as CD34 and GlyCAM-1 (not shown), on the high endothelial venule (HEV, upper panel). After encounter with antigen, many of the differentiated effector T cells lose expression of L-selectin, leave the lymph node about 4–5 days later, and now express the integrin VLA-4 and increased levels of LFA-1 (not shown). These bind to VCAM-1 and ICAM-1, respectively, on peripheral vascular endothelium at sites of inflammation (lower panel). On differentiating into effector cells, T cells also alter their splicing of the mRNA encoding the cell-surface protein CD45. The CD45RO isoform expressed by effector T cells lacks one or more exons that encode extracellular domains present in the CD45RA isoform expressed by naive T cells, and somehow makes effector T cells more


Immunology_Janeway

Immunology_Janeway. isoform expressed by effector T cells lacks one or more exons that encode extracellular domains present in the CD45RA isoform expressed by naive T cells, and somehow makes effector T cells more sensitive to stimulation by specific antigen.


Immunology_Janeway

Immunology_Janeway. of naive T cells in order to retain the developing effector cells in the lymphoid tissue as they undergo differentiation and clonal expansion (see Section 9-6). Most effector T cells also shed L-selectin, which mediates rolling on the high endothelial venules of secondary lymphoid tissues such as lymph nodes, in favor of P-selectin glycoprotein ligand-1 (PSGL-1), a homodimeric sialoglycoprotein that is the major ligand for tethering and rolling on the Pand E-selectin expressed by activated endothelial cells at sites of inflammation (Fig. 11.6). In contrast to granulocytes and monocytes, which constitutively express glycosyltransferases necessary for biosynthesis of selectin ligands, T cells express these enzymes only after effector T-cell development. Effector differentiation induces expression of the glycosyltransferase α1,3-fucosyltransferase VII (FucT-VII), a key enzyme required for both Pand E-selectin ligand generation. Thus, although PSGL-1 is expressed by both naive and


Immunology_Janeway

Immunology_Janeway. expression of the glycosyltransferase α1,3-fucosyltransferase VII (FucT-VII), a key enzyme required for both Pand E-selectin ligand generation. Thus, although PSGL-1 is expressed by both naive and effector T cells, it is appropriately glycosylated for selectin binding only by effector T cells.


Immunology_Janeway

Immunology_Janeway. The expression of other adhesion molecules such as integrins that are important for the recruitment of effector T cells to inflamed tissues is also increased (see Fig. 11.6). Naive T cells mainly express LFA-1 (αLβ2), which is retained on effector T cells as they develop from naive T-cell precursors. However, LFA-1 is not the only integrin that these cells express. Effector T cells also synthesize the integrin α4:β1, or VLA-4, which binds to the adhesion molecule VCAM-1, a member of the immunoglobulin superfamily related to ICAM-1. When T cells are activated by chemokine signaling, VLA-4 is altered so that it can bind to VCAM-1 with greater affinity, similar to chemokine-induced binding of activated LFA-1 to ICAM-1 (see Section 3-18). Thus, chemokines activate VCAM-1 to bind VLA-4 on vascular endothelial cells near sites of inflammation, allowing extravasation of effector T cells. Although both VCAM-1 and ICAM-1 are expressed on activated endothelial cell surfaces, there appears to be


Immunology_Janeway

Immunology_Janeway. endothelial cells near sites of inflammation, allowing extravasation of effector T cells. Although both VCAM-1 and ICAM-1 are expressed on activated endothelial cell surfaces, there appears to be preferential utilization of one of the two adhesion pairs in some inflamed tissue vascular beds: recruitment of effector T cells is more dependent on VLA-4 in some tissues, and more dependent on LFA-1 in others.


Immunology_Janeway

Immunology_Janeway. Induction of expression of some adhesion molecules is compartmentalized so that effector T cells primed within lymphoid compartments of those tissues home back to them, whether during an active immune response or at homeostasis. Thus, the site of priming appears to imprint effector T cells with the ability to traffic to particular tissues. This is achieved by the expression of adhesion molecules that bind selectively to tissue-specific addressins. In this context, the adhesion molecules are often known as homing receptors (Fig. 11.7). As we shall see in Chapter 12, dendritic cells that prime T cells in the gut-associated lymphoid tissues (GALT) induce expression of the α4:β7 integrin, which binds to the mucosal vascular addressin MAdCAM-1 that is constitutively expressed by endothelial cells of blood vessels within the gut mucosa (see Fig. 11.7, lower left panel).


Immunology_Janeway

Immunology_Janeway. T cells primed in the GALT also express specific chemokine receptors that bind chemokines produced constitutively—and specifically—by the gut epithelium. Thus, at homeostasis CCR9 expressed on T cells primed in lymphoid Intestinal epithelial cells express CCL25, which binds CCR9 on gut-homing effector T cell CCL25CCR9˜4:°7integrinCCL25bloodvesselLymphocytes homing to the small intestine bind MAdCAM-1 and the chemokine CCL25 on vascular endothelium laminapropriaintestinalepitheliumCCR9MAdCAM-1˜4:°7


Immunology_Janeway

Immunology_Janeway. Fig. 11.7 Skinand gut-homing T cells use particular combinations of integrins and chemokines to migrate specifically to their target tissues. α4β7 expressed on circulating lymphocytes primed in gut-associated lymphoid tissues initally binds MAdCAM-1 (upper left panel), then uses CCR9 to move along a CCL25 chemokine gradient to traverse the endothelium and migrate to the intestinal epothelium (upper right panel). Similarly, circulating lymphocytes primed in lymph nodes draining the skin bind to the endothelium lining a cutaneous blood vessel by interactions between cutaneous lymphocyte antigen (CLA) and constitutively expressed E-selectin on the endothelial cells (lower left panel). The adhesion is strengthened by an interaction between lymphocyte chemokine receptor CCR4 and the endothelial chemokine CCL17. Once through the endothelium, effector T lymphocytes are attracted to keratinocytes of the epidermis by the chemokine CCL27, which binds to the receptor CCR10 on lymphocytes (lower


Immunology_Janeway

Immunology_Janeway. chemokine CCL17. Once through the endothelium, effector T lymphocytes are attracted to keratinocytes of the epidermis by the chemokine CCL27, which binds to the receptor CCR10 on lymphocytes (lower right panel).


Immunology_Janeway

Immunology_Janeway. tissues of the small intestine recruits those T cells back to the lamina propria subjacent to the epithelium of the small intestine along a CCL25 gradient (see Fig. 11.7, upper right panel). In contrast, T cells primed in skin-draining lymph nodes preferentially home back to the skin. They are induced to express the adhesion molecule cutaneous lymphocyte antigen (CLA), an isoform of PSGL-1 that differs in its pattern of glycosylation and binds to E-selectin on cutaneous vascular endothelium (see Fig. 11.7, lower panels). CLA-expressing T lymphocytes also express the chemokine receptors CCR4 and CCR10, which bind sequentially the chemokines CCL17 (TARC) and CCL27 (CTACK), respectively, which are present at highest levels in cutaneous blood vessels and the epidermis. Because these tissue-homing chemokines are produced at steady state, they are referred to as homeostatic chemokines. They are analogous to chemokines produced constitutively in lymphoid tissues at steady state, such as


Immunology_Janeway

Immunology_Janeway. chemokines are produced at steady state, they are referred to as homeostatic chemokines. They are analogous to chemokines produced constitutively in lymphoid tissues at steady state, such as CCL19 and CCL21, that direct CCR7-bearing naive T cells along a gradient from the endothelium of HEVs to T-cell zones (Fig. 11.8). Homeostatic chemokines are to be contrasted with inflammatory chemokines, which are elicited in the context of infection to recruit circulating immune cells to sites of inflammation.


Immunology_Janeway

Immunology_Janeway. Chemokines are classified into four families on the basis of structural differences: CXCL, CCL, XCL, and CXC3CL. Chemokines can also be classified as pro-inflammatory (red), homeostatic (green), and mixed function (yellow). Chemokines bind to a subfamily of seven-transmembrane G-protein-coupled receptors, which are classified as CXCR, CCR, XCR, and CX3CR on the basis of the class of chemokines they bind. Many, but not all, of the chemokine-chemokine receptor networks that coordinate immune modules are represented here. The connection between receptors and cell types on which they are expressed is indicated by the ‘circuit’ representation of lines and connecting nodes. To connect chemokines and their receptors to target cells, follow a horizontal line and turn on a vertical one at each node; the rhomboids (diamond shapes) link vertical lines to the cell type. Note that most chemokine receptors can bind multiple chemokines. Modified from Mantovani et al., Nat. Rev. Immunol. 2006,


Immunology_Janeway

Immunology_Janeway. node; the rhomboids (diamond shapes) link vertical lines to the cell type. Note that most chemokine receptors can bind multiple chemokines. Modified from Mantovani et al., Nat. Rev. Immunol. 2006, 6:907-918.


Immunology_Janeway

Immunology_Janeway. Fig. 11.8 Chemokine networks coordinate the interactions of innate and adaptive immune-cell populations.


Immunology_Janeway

Immunology_Janeway. In addition to the general and tissue-specific changes in trafficking molecules induced during effector T-cell differentiation, there is subset-specific expression of chemokine receptors that accompanies the loss of CCR7 expression. This results in distinct patterns of chemokine receptor expression by TH1, TH2, and TH17 cells that guide their differential recruitment to sites of inflammation contingent on the local patterns of inflammatory chemokines induced by the innate immune response to different types of pathogens (Fig. 11.9). For example, TH1 cells express CCR5, which is also expressed on monocytes that mature into macrophages as they enter the inflammatory site. Thus, both TH1 cells and the innate effector cells whose effector functions they enhance are recruited to the same tissue site by the same chemokines (see Fig. 11.8). As is the case for many other chemokine receptors, CCR5 has multiple ligands (CCL3, CCL4, CCL5, and CCL8), which may be induced by different cellular


Immunology_Janeway

Immunology_Janeway. site by the same chemokines (see Fig. 11.8). As is the case for many other chemokine receptors, CCR5 has multiple ligands (CCL3, CCL4, CCL5, and CCL8), which may be induced by different cellular sources and by different pathogens targeted by type 1 immunity. Some of these are produced by activated macrophages themselves following their recruitment to the inflammatory site. This provides a feed-forward mechanism by which the emerging innate response is amplified and then contributes to the recruitment of TH1 cells, which then provide antigen-dependent ‘help’ to further activate the macrophages, as we discuss in the next section. TH1 cells also express CXCR3, which is shared by NK cells and cytotoxic CD8 T cells. In response to CXCR3 ligands— CXCL9 and CXCL10—these cells are recruited to the same inflammatory site to coordinate the cell-mediated killing of targets infected by intracellular patho gens, such as Listeria monocytogenes, or certain viruses.


Immunology_Janeway

Immunology_Janeway. TH2 and TH17 cells display different patterns of inflammatory chemokine receptors, some of which, like those expressed by TH1 cells, are shared with the myelomonocytic cells with which they interact in inflamed tissues (see Figs. 11.8 and 11.9). The shared expression pattern of chemokine receptors by innate and adaptive effector cells represents an important mechanism for the spatiotemporal coordination and integration of immune effector modules in response to different types of pathogen (see Fig. 11.8). Thus, the local release of cytokines and chemokines at the site of infection has far-reaching consequences. In addition to recruiting granulocytes and monocytes, which constitutively express their specific complement of chemokine receptors while in circulation, changes induced in the blood vessel walls also enable newly generated effector T lymphocytes to enter infected tissues. Once in the tissue, recruited T cells produce T helper cell type–specific cytokines that further increase


Immunology_Janeway

Immunology_Janeway. vessel walls also enable newly generated effector T lymphocytes to enter infected tissues. Once in the tissue, recruited T cells produce T helper cell type–specific cytokines that further increase specific chemokine production by innate immune cells in an additional feed-forward mechanism that results in further effector T cell and innate effector cell trafficking into the tissue. Because the cytokines that differentially drive local production of effector module-specific chemokines are similarly produced by ILCs, this represents another major function of ILCs in coordinating the early polarization of pathogen-specific responses.


Immunology_Janeway

Immunology_Janeway. 11-4 Pathogen-specific effector T cells are enriched at sites of infection as adaptive immunity progresses.


Immunology_Janeway

Immunology_Janeway. In the early stage of the adaptive immune response, only a minority of the effector T cells that enter infected tissues will be specific for pathogen. This is because activation of the endothelium of local blood vessels by inflammatory cytokines induces expression of selectins, integrin ligands, and chemokines that can recruit any circulating effector or memory T cell that expresses the appropriate trafficking receptors, irrespective of its antigenic specificity. However, specificity of the reaction is rapidly increased as the number of pathogen-specific T cells increases and recognition of antigen within the inflamed tissue retains them there. Although the precise mechanisms controlling retention of antigen-activated effector T cells in the inflamed tissue are not entirely understood, it is thought that the same mechanisms that retain antigen-activated naive T cells within secondary lymphoid tissues during effector


Immunology_Janeway

Immunology_Janeway. Fig. 11.9 The expression of adhesion and chemokine receptors is altered during effector T cell differentiation. During a primary immune response, specific cytokines derived from the innate immune system (indicated along the three diverging arrows) and unique master transcription factors (T-bet, GATA3, and RORγt) direct naive CD4 T cells to differentiate into TH1, TH2, or TH17 effector cells. Effector T cells of each subset lose expression of L-selectin (CD62L) and CCR7, and express characteristic chemokine receptors. Fig. 11.10 TH1 cells activate macrophages to become highly microbicidal. When an effector TH1 cell specific for a bacterial peptide contacts an infected macrophage, the T cell is induced to secrete the macrophage-activating factor IFN-γ and to express CD40 ligand. Together these newly synthesized TH1 proteins activate the macrophage.


Immunology_Janeway

Immunology_Janeway. T-cell development might be at play. This includes a role for the S1P pathway, although other chemokine signals may participate. By the peak of an adaptive immune response, after several days of clonal expansion and differentiation, a large fraction of the recruited T cells will be specific for the infecting pathogen.


Immunology_Janeway

Immunology_Janeway. Effector T cells that enter tissues but do not recognize their cognate antigen are not retained there. They either undergo apoptosis locally or enter the afferent lymphatics and migrate to the draining lymph nodes and eventually return to the bloodstream. Thus, T cells in the afferent lymph that drains tissues are memory or effector T cells, which characteristically express the CD45RO isoform of the cell-surface molecule CD45 and lack L-selectin (see Fig. 11.6). Effector T cells and some memory T cells have similar trafficking phenotypes, as we discuss later (see Section 11-22), and both seem to be committed to migration through, and in some cases, retention within, barrier tissues that are the primary sites of infection. In addition to allowing effector T cells to clear all sites of infection, this pattern of migration allows them to contribute, along with memory cells, to protecting the host against reinfection with the same pathogen.


Immunology_Janeway

Immunology_Janeway. 11-5 TH1 cells coordinate and amplify the host response to intracellular pathogens through classical activation of macrophages.


Immunology_Janeway

Immunology_Janeway. Type 1 responses (see Fig. 11.5) are important for the eradication of those pathogens that have evolved mechanisms to survive and replicate within macrophages—for example, viruses, and bacterial and protozoan pathogens that can survive inside macrophage intracellular vesicles. In the case of viruses, a TH1 response is generally involved in helping to activate the CD8 cytotoxic T cells that will recognize virus-infected cells and destroy them (see Chapter 9). TFH cells that differentiate in type 1 responses induce the production of subclasses of IgG antibodies that neutralize virus particles in the blood and extracellular fluid. In the case of intracellular bacteria such as mycobacteria and Salmonella, and of protozoa such as Leishmania and Toxoplasma, which all take up residence inside macrophages, the role of TH1 cells is to activate macrophages to heighten their microbicidal function (Fig 11.10).


Immunology_Janeway

Immunology_Janeway. Pathogens of all types are ingested by macrophages from the extracellular fluid, and are often destroyed without the need for additional macrophage activation. In several clinically important infections, such as those caused by mycobacteria, ingested pathogens are not killed, and can even set up a chronic infection in macrophages and incapacitate them. Such microorganisms are able to maintain themselves in the hostile environment of phagosomes— shielded from the effects of both antibodies and cytotoxic T cells—by inhibiting the fusion of phagosomes and lysosomes, or by preventing the acidification required to activate lysosomal proteases. Nevertheless, peptides derived from such microorganisms can be displayed by MHC class II molecules on the macrophage surface, where they are recognized by antigen-specific effector TH1 cells. The TH1 cell is stimulated to synthesize membrane-associated proteins and soluble cytokines that enhance the macrophage’s antimicrobial defenses and enable it


Immunology_Janeway

Immunology_Janeway. by antigen-specific effector TH1 cells. The TH1 cell is stimulated to synthesize membrane-associated proteins and soluble cytokines that enhance the macrophage’s antimicrobial defenses and enable it to either eliminate the pathogen or control its growth and spread. This boost to antimicrobial mechanisms is known as ‘classical’ macrophage activation, the result of which is the so-called classically-activated, or M1, macrophage (Fig. 11.11).


Immunology_Janeway

Immunology_Janeway. Macrophages require two main signals for classical activation, and effector TH1 cells can deliver both. One signal is the cytokine IFN-γ; the other, CD40L, sensitizes the macrophage to respond to IFN-γ (see Fig. 11.10). TH1 cells also secrete lymphotoxin, which can substitute for CD40 ligand in M1 macrophage activation. The M1 macrophage is a potent antimicrobial effector cell. Phagosomes fuse with lysosomes, and microbicidal reactive oxygen and Fig. 11.11 Macrophages activated by TH1 cells undergo changes that greatly increase their antimicrobial effectiveness and amplify the immune response.


Immunology_Janeway

Immunology_Janeway. Fig. 11.11 Macrophages activated by TH1 cells undergo changes that greatly increase their antimicrobial effectiveness and amplify the immune response. Activated macrophages increase their expression of CD40 and of TNF receptors, and are stimulated to secrete TNF-α. This autocrine stimulus synergizes with IFN-γ secreted by TH1 cells to induce classical, or M1, macrophage activation characterized by the production of nitric oxide (NO) and superoxide (O2–). The macrophage also upregulates its B7 molecules in response to binding to CD40 ligand on the T cell, and increases its expression of MHC class II molecules in response to IFN-γ, thus allowing further activation of resting CD4 T cells.


Immunology_Janeway

Immunology_Janeway. nitrogen species are generated, as described in Section 3-2. When TH1 cells stimulate macrophages through these molecules, the M1 macrophage also secretes TNF-α, further stimulating macrophages through the TNFR-I, the same receptor activated by LT-α. TNF receptor signalling seems to be required to maintain the viability of the macrophage in this setting; in mice lacking TNFR-I (see Section 9-28), infection by Mycobacterium avium, an opportunistic intracellular pathogen that does not normally cause disease, leads to excessive apoptosis of macrophages that results in the release and dissemination of the pathogen before it can be killed within the infected macrophage. CD8 T cells also produce IFN-γ and can activate macrophages presenting antigens derived from cytosolic proteins on MHC class I molecules. Macrophages can also be made more sensitive to IFN-γ by very small amounts of bacterial LPS, and this latter pathway may be particularly important when CD8 T cells are the primary source


Immunology_Janeway

Immunology_Janeway. I molecules. Macrophages can also be made more sensitive to IFN-γ by very small amounts of bacterial LPS, and this latter pathway may be particularly important when CD8 T cells are the primary source of the IFN-γ.


Immunology_Janeway

Immunology_Janeway. In addition to increased intracellular killing, TH1 cells induce other changes in macrophages that help to amplify the adaptive immune response against intracellular pathogens. These changes include an increase in the number of MHC class II molecules, B7 molecules, CD40, and TNF receptors on the M1 macrophage surface (see Figs. 11.10 and 11.11), making the cell more effective at presenting antigen to T cells, and more responsive to CD40 ligand and TNF-α. In addition, M1 macrophages secrete IL-12, which increases the amount of IFN-γ produced by ILC1s and TH1 cells. This also promotes the differentiation of activated naive CD4 T cells into TH1 effector cells, and naive CD8 T cells into cytotoxic effectors (see Sections 9-20 and 9-18).


Immunology_Janeway

Immunology_Janeway. Another important function of TH1 cells is the recruitment of additional phagocytic cells to sites of infection. TH1 cells recruit macrophages by two mechanisms (Fig. 11.12). First, they make the hematopoietic growth factors IL-3 and GM-CSF, which stimulate the production of new monocytes in the bone marrow. Second, the TNF-α and lymphotoxin secreted by TH1 cells at sites of infection change the surface properties of endothelial cells so that monocytes adhere to them. Chemokines such as CCL2, which are induced by TH1 cells at inflammatory sites, direct the migration of monocytes through the vascular endothelium and into the infected tissue, where they differentiate into macrophages (see Section 3-17). Cytokines and chemokines secreted by M1 macrophages themselves are also important in recruiting other monocytes to sites of infection. Collectively, these TH1-mediated effects provide a positive feedback loop that amplifies and sustains type 1 responses until the pathogen is controlled


Immunology_Janeway

Immunology_Janeway. other monocytes to sites of infection. Collectively, these TH1-mediated effects provide a positive feedback loop that amplifies and sustains type 1 responses until the pathogen is controlled or eliminated.


Immunology_Janeway

Immunology_Janeway. Certain intravesicular bacteria, including some mycobacteria and Listeria monocytogenes, escape from phagocytic vesicles and enter the cytoplasm, where they are no longer susceptible to the microbicidal actions of activated macrophages. Their presence can, however, be detected by cytotoxic CD8 T cells. The pathogens released when macrophages are killed by these CTLs can be killed in the extracellular environment by antibody-mediated mechanisms, or can be phagocytosed by freshly recruited macrophages. In this circumstance, the provision of TH1-mediated ‘help’ for the development of CTLs, such as the provision of IL-2, may play an important role in coordinating the TH1 and CTL responses.


Immunology_Janeway

Immunology_Janeway. Fig. 11.12 The immune response to intracellular bacteria is differrentiation and potentiates the release of other cytokines. IL-3 coordinated by activated TH1 cells. The activation of TH1 cells and GM-CSF stimulate the production of new monocytes by acting by infected macrophages results in the synthesis of cytokines that on hematopoietic stem cells in the bone marrow. New macrophages both induce M1 macrophage and coordinate the immune response are recruited to the site of infection by the actions of secreted to intracellular pathogens. IFN-γ and CD40 ligand synergize in TNF-α, LT-α, and other cytokines on vascular endothelium, which activating the macrophage, which allows it to kill engulfed pathogens. signal monocytes to leave the bloodstream and enter the tissues Chronically infected macrophages lose the ability to kill intracellular where they become macrophages. A chemokine with monocyte bacteria, and membrane-bound Fas ligand or LT-β produced by chemotactic activity (CCL2)


Immunology_Janeway

Immunology_Janeway. macrophages lose the ability to kill intracellular where they become macrophages. A chemokine with monocyte bacteria, and membrane-bound Fas ligand or LT-β produced by chemotactic activity (CCL2) signals monocytes to migrate into sites the TH1 cell can kill these macrophages, releasing the engulfed of infection and accumulate there. Thus, the TH1 cell coordinates bacteria, which are taken up and killed by fresh macrophages. In a macrophage response that is highly effective in destroying this way, IFN-γ and LT-β synergize in the removal of intracellular intracellular infectious agents. bacteria. IL-2 produced by TH1 cells augments effector T-cell 11-6 Activation of macrophages by TH1 cells must be tightly regulated to avoid tissue damage.


Immunology_Janeway

Immunology_Janeway. As discussed in Chapter 9, distinguishing features of effector T cells are their capacity for antigen-induced activation of effector functions without the requirement for co-stimulation, and also their efficient delivery of effector molecules through polarized secretion or expression of cytokines and cell-surface molecules—often through formation of an immunological synapse with an antigen-bearing cell (see Section 9-25). After a TH1 cell recognizes its cognate antigen expressed by a macrophage, the secretion of effector molecules requires several hours. TH1 cells must therefore adhere to their target cells far longer than do cytotoxic CD8 T cells. Similarly to cytotoxic T cells, the secretory machinery of the TH1 cell becomes oriented toward the site of contact with the macrophage and newly synthesized cytokines are secreted there (see Fig. 9.38). CD40 ligand also seems to be delivered to the same contact site. So although all macrophages have receptors for IFN-γ, the infected


Immunology_Janeway

Immunology_Janeway. and newly synthesized cytokines are secreted there (see Fig. 9.38). CD40 ligand also seems to be delivered to the same contact site. So although all macrophages have receptors for IFN-γ, the infected macrophage that presents antigen to the TH1 cell is far more likely to become activated than nearby uninfected macrophages.


Immunology_Janeway

Immunology_Janeway. In addition to more efficiently focusing activating signals on infected macrophages, the antigen-specific induction of macrophage activation may play an important role in limiting tissue injury. By targeting only infected macrophages through MHC:peptide recognition, TH1 cells minimize ‘collateral damage’ that might otherwise result to normal components of the inflamed tissue: oxygen radicals, NO, and proteases that are toxic to host cells as well as to the pathogen that is targeted for destruction. Thus, antigen-specific macrophage activation by TH1 cells is a means of deploying this powerful defensive mechanism to maximum effect while minimizing local tissue damage. In this regard, it is notable that although ILC1s are also producers of IFN-γ, they lack antigen receptors that can focus the cytokine on infected macrophages for more efficient activation. It is not yet known whether ILC1 cells have other mechanisms with which to direct IFN-γ onto macrophages, or whether they play a more


Immunology_Janeway

Immunology_Janeway. cytokine on infected macrophages for more efficient activation. It is not yet known whether ILC1 cells have other mechanisms with which to direct IFN-γ onto macrophages, or whether they play a more limited role in macrophage activation, but the IFN-γ they produce is important in indirectly enhancing the local inflammatory response.


Immunology_Janeway

Immunology_Janeway. 11-7 Chronic activation of macrophages by TH1 cells mediates the formation of granulomas to contain intracellular pathogens that cannot be cleared.


Immunology_Janeway

Immunology_Janeway. Some intracellular pathogens, most notably Mycobacterium tuberculosis, are sufficiently resistant to the microbicidal effects of activated macrophages that they are incompletely eliminated by a type 1 response. This gives rise to chronic, low-level infection that requires an ongoing TH1 response to prevent pathogen proliferation and spread. In this circumstance, chronic coordination between TH1 cells and macrophages underlies the formation of the immunological reaction called the granuloma, in which microbes are held in check within a central area of macrophages surrounded by activated lymphocytes (Fig. 11.13). A characteristic feature of granulomas is the fusion of several macrophages to form multinucleated giant cells, which can be found at the border of the central focus of activated macrophages and the lymphocytes that surround them and which appear to have heightened antimicrobial activity. A granuloma serves to ‘wall off’ pathogens that resist destruction. In tuberculosis, the


Immunology_Janeway

Immunology_Janeway. macrophages and the lymphocytes that surround them and which appear to have heightened antimicrobial activity. A granuloma serves to ‘wall off’ pathogens that resist destruction. In tuberculosis, the centers of large granulomas can become isolated and the cells there die, probably from a combination of lack of oxygen and the cytotoxic effects of activated macrophages. As the dead tissue in the center resembles cheese, this process is called ‘caseous’ necrosis. Thus, the chronic activation of TH1 cells can cause significant pathology. The absence of the TH1 response, however, leads to the more serious consequence of death from disseminated infection, which is now seen frequently in patients with AIDS and concomitant mycobacterial infection.


Immunology_Janeway

Immunology_Janeway. 11-8 Defects in type 1 immunity reveal its important role in the elimination of intracellular pathogens. In mice whose gene for IFN-γor CD40 ligand has been deleted by gene targeting, classical macrophage activation is impaired; consequently, the animals succumb to sublethal doses of Mycobacterium, Salmonella, and Leishmania species. Classical (M1) macrophage activation is also crucial in controlling vaccinia virus. However, although IFN-γ and CD40 ligand are probably the most important effector molecules synthesized by TH1 cells, the immune response to pathogens that proliferate in macrophage vesicles is complex, and other cytokines secreted by TH1 cells may also be crucial (see Fig. 11.12).


Immunology_Janeway

Immunology_Janeway. The depletion of CD4 T cells in people with HIV/AIDS causes ineffective TH1 responses that can lead to the dissemination of microbes that are normally cleared by macrophages. This is the case with the opportunist fungal pathogen Pneumocystis jirovecii (see also Chapter 13). The lungs of healthy people are kept clear of P. jirovecii by phagocytosis and intracellular killing by alveolar macrophages. Pneumonia caused by P. jirovecii is, however, a frequent cause of death in people with AIDS. In the absence of CD4 T cells, phagocytosis of P. jirovecii and intracellular killing by lung macrophages are impaired, and the Granuloma multi-nucleated giant cell epithelioid cell T cells mycobacteria IFN-˜Partial removal of live M. tuberculosis TH1


Immunology_Janeway

Immunology_Janeway. Fig. 11.13 Granulomas form when an intracellular pathogen or its constituents cannot be completely eliminated. When mycobacteria (red) resist the effects of macrophage activation, a characteristic localized inflammatory response called a granuloma develops. This consists of a central core of infected macrophages. The core may include multinucleate giant cells, which are fused macrophages, surrounded by large macrophages often called epithelioid cells, but in granulomas caused by mycobacteria the core usually becomes necrotic. Mycobacteria can persist in the cells of the granuloma. The central core is surrounded by T cells, many of which are CD4-positive. The exact mechanisms by which this balance is achieved, and how it breaks down, are unknown. Granulomas, as seen in the bottom panel, also form in the lungs and elsewhere in a disease known as sarcoidosis, which may be caused by inapparent mycobacterial infection. Photograph courtesy of J. Orrell.


Immunology_Janeway

Immunology_Janeway. Panel a: the whipworm Trichuris trichiura is a helminth parasite that lives partly embedded in intestinal epithelial cells. This scanning electron micrograph of mouse colon shows the head of the parasite buried in an epithelial cell and its posterior lying free in the lumen. Panel b: a cross-section of crypts from the colon of a mouse infected with T. trichiura shows the markedly increased production of mucus by goblet cells in the intestinal epithelium. The mucus is seen as large droplets in vesicles inside the goblet cells and stains dark blue with periodic acid–Schiff reagent. Magnification ×400. pathogen colonizes the surface of the lung epithelium and invades lung tissue. The requirement for CD4 T cells seems to be due, at least in part, to a requirement for the macrophage-activating cytokines IFN-γ and TNF-α produced by TH1 cells. 11-9 TH2 cells coordinate type 2 responses to expel intestinal helminths and repair tissue injury.


Immunology_Janeway

Immunology_Janeway. Type 2 immunity is directed against parasitic helminths: roundworms (nematodes) and two types of flatworms—tapeworms (cestodes) and flukes (trematodes). Unlike microbial pathogens, or ‘micropathogens’ (bacteria, viruses, fungi, and protozoa), which replicate rapidly and can overwhelm host defenses by sheer numbers, most helminths do not replicate in their mammalian host. Moreover, helminths are multicellular; they are metazoan ‘macropathogens’ that are far too large—ranging in size from approximately 1 mm to over 1 meter—to be engulfed by host phagocytic cells, and therefore require very different strategies for host defense. In the developing world, the intestines of virtually all animals and humans are colonized by helminth parasites (Fig. 11.14). Many of these infections may be cleared rapidly by the generation of an effective type 2 response, although often the host response is successful in reducing worm burden, but not in completely clearing the parasite, resulting in chronic


Immunology_Janeway

Immunology_Janeway. rapidly by the generation of an effective type 2 response, although often the host response is successful in reducing worm burden, but not in completely clearing the parasite, resulting in chronic disease. In these circumstances, the parasite persists for long periods despite the host’s attempts to expel it, and causes disease by competing with the host for nutrients, or by causing local tissue injury.


Immunology_Janeway

Immunology_Janeway. Irrespective of the type of helminth involved, or its site of host entry, the host adaptive response is orchestrated by TH2 cells (Fig. 11.15; see also Fig. 9.30). The TH2 response is induced by the actions of worm products on a variety of different innate cells: epithelial cells, ILC2 cells, mast cells, and dendritic cells. Dendritic cells required for the presentation of helminth antigens to naive CD4 T cells appear to be activated by IL-13 produced by ILC2 cells and innate cytokines, such as epithelium-derived TSLP, which repress the development of TH1and TH17-inducing dendritic cells in favor of dendritic cells that promote TH2 cell differentiation. The initial source of the IL-4 required for TH2 cell differentiation appears to be context-specific and redundant. Thus, although several cell types have been proposed as the source, including iNKT cells, mast cells, and basophils, none of these has been proven to be essential.


Immunology_Janeway

Immunology_Janeway. The development of TH2 cells in draining lymphoid tissues is followed by their exodus to sites of helminth invasion, where they enhance the recruitment and function of circulating type 2 innate effector cells—eosinophils, basophils, tissue mast cells, and macrophages. Like TH1 and TH17 cells, TH2 cells express a distinct complement of chemokine receptors that is shared with the circulating innate effector cells with which they interact, thus selectively guiding them to sites of ongoing type 2 responses (see Figs. 11.8 and 11.9). CCR3 and CCR4 are expressed both by TH2 cells and by eosinophils and basophils, as is CRTH2, the ligand for which is prostaglandin D2, a lipid mediator that is produced by activated tissue mast cells. Ligands for CCR3 (for example, the eotaxins CCL11, CCL24, and CCL26) are produced by multiple innate immune cells in tissue sites of helminth infection and are induced by IL-4 and IL-13 signaling. Hence, ILC2 cells, TH2 cells, and eosinophils and basophils can


Immunology_Janeway

Immunology_Janeway. CCL26) are produced by multiple innate immune cells in tissue sites of helminth infection and are induced by IL-4 and IL-13 signaling. Hence, ILC2 cells, TH2 cells, and eosinophils and basophils can each amplify the recruitment of other type 2 cells through this chemokine network.


Immunology_Janeway

Immunology_Janeway. Although the TH2 effector response can coordinate the direct killing of some worms by enhancing innate effector cell functions, a major focus of the antihelminth response is expelling the worms and limiting the tissue damage they cause when they invade the host—functions that are both mediated by type 2 cytokines. IL-13 directly enhances the production of mucus by goblet cells, activates smooth muscle cells in mucosal tissues for hypermotility, and increases the migration and turnover of epithelial cells in the mucosa (see Fig. 11.15, first panel). In the intestines, which are the most common site of worm infestation, each of these actions is a critical component of the host response, as it helps to eliminate parasites that have attached to the epithelium and decreases the surface area available for colonization.


Immunology_Janeway

Immunology_Janeway. The response to helminths generates high levels of IgE antibody, induced by IL-4-producing TFH cells that develop in concert with TH2 cells (see Section 9-20). IgE binds to Fcεreceptors expressed by mast cells, eosinophils, and basophils, which arms them for antigen-specific recognition and activation. Type 2 adaptive responses also promote production of IgG1, which is recognized by macrophages and engages them in the type 2 response. IL-4 and IL-13 produced by TH2 cells also result in the differentiation of alternatively activated macrophages (also called M2 macrophages). Unlike classically activated, M1 macrophages, which differentiate after interaction with TH1 cells and are potent activators of inflammation (see Fig. 11.10), M2 macrophages participate in worm killing and expulsion, and also promote tissue remodeling and repair (see Fig. 11.15). A major difference between M1 and M2 macrophages is their different metabolism of arginine to produce antipathogen products. Whereas M1


Immunology_Janeway

Immunology_Janeway. and also promote tissue remodeling and repair (see Fig. 11.15). A major difference between M1 and M2 macrophages is their different metabolism of arginine to produce antipathogen products. Whereas M1 macrophages express iNOS, which produces the potent intracellular microbicide nitric oxide (NO) (see Section 3-2), M2 macrophages express arginase-1, which produces ornithine and proline from arginine. Along with other factors, ornithine increases the contractility of mucosal smooth muscle and promotes tissue remodeling and repair (see Fig. 11.15). Through a mechanism that is unclear, ornithine has also been found to be directly toxic to IgG-coated larvae of certain helminths. Because helminths that have invaded tissues are too large to be ingested by macrophages, the targeted release of toxic mediators directly onto the worm by antibody-dependent cell-mediated cytotoxicity (ADCC) enables macrophages, as well as eosinophils (see below), to attack these large extracellular pathogens.


Immunology_Janeway

Immunology_Janeway. Macrophages activated by TH2 cells also appear to be important in walling off invading worms, as well as repairing tissue damage caused as worms migrate through host tissues. These ‘tissue repair’ functions of M2 macrophages are dependent on secreted factors important in tissue remodeling and include the stimulation of collagen production, formation of which requires proline that is generated by arginase-1 activity. Moreover, TH2-activated macrophages can also induce the formation of granulomas that entrap worm larvae in tissues. In this regard, antigen-specific macrophage activation by TH2 cells has non-redundant function in type 2 responses. Although ILC2 cells, and innate effector cells, may promote M2 macrophage activation via IL-13, they are unable to sustain this response. Thus, in several models of worm infection, antihelminth responses are considerably impaired in RAG-deficient or T-cell-depleted mice, demonstrating that sustained alternative activation of macrophages requires


Immunology_Janeway

Immunology_Janeway. models of worm infection, antihelminth responses are considerably impaired in RAG-deficient or T-cell-depleted mice, demonstrating that sustained alternative activation of macrophages requires TH2 cells.


Immunology_Janeway

Immunology_Janeway. The IL-5 produced by TH2 cells and ILC2 cells recruits and activates eosinophils (see Fig. 11.15), which have direct toxic effects on worms by releasing cytotoxic molecules stored in their secretory granules, such as major basic protein (MBP). In addition to Fcε receptors that arm them for degranulation with IgE, eosinophils bear Fc receptors for IgG and can mediate ADCC against IgGcoated parasites (see Fig. 10.38). They also express the Fcα receptor (CD89) and degranulate in response to stimulation by secretory IgA.


Immunology_Janeway

Immunology_Janeway. IL-3 and IL-9 produced by TH2 cells in the mucosae recruit, expand, and activate a specialized population of mast cells known as mucosal mast cells (see Fig. 11.15). The innate cytokines IL-25 and IL-33 also activate mucosal mast cells early in a response to helminths. Mucosal mast cells differ from their counterparts in other tissues by having only small numbers of IgE receptors and producing very little histamine. When activated by cytokines, or by the binding of worm antigens to receptor-bound IgE, mucosal mast cells release large amounts of preformed inflammatory mediators that are stored in secretory granules: prostaglandins, leukotrienes, and several proteases, including the mucosal mast cell protease (MMCP-1), which can degrade the epithelial tight junctions to increase permeability and fluid flow into the mucosal lumen. Together, the mast-cell-derived mediators increase vascular and epithelial permeability, increase intestinal motility, stimulate the production of mucus by


Immunology_Janeway

Immunology_Janeway. and fluid flow into the mucosal lumen. Together, the mast-cell-derived mediators increase vascular and epithelial permeability, increase intestinal motility, stimulate the production of mucus by goblet cells, and induce leukocyte recruitment, all of which contribute to the ‘weep and sweep’ response that helps to expel parasites from the host.


Immunology_Janeway

Immunology_Janeway. 11-10 TH17 cells coordinate type 3 responses to enhance the clearance of extracellular bacteria and fungi. The subset of effector T cells generated in response to infection by extracellular bacteria and fungi is TH17. At homeostasis, TH17 cells are deployed almost exclusively in the intestinal mucosa, where they contribute to the mutualistic relationship between the host and the intestinal microbiota—which is composed of extracellular bacteria and some fungi. However, they are also critical for defense against pathogenic extracellular bacteria and fungi that invade at barrier sites, as well as components of the normal microbiota that may enter the host when epithelial barrier function is compromised, whether as the result of trauma or pathogenic infection. In these settings, a principal function of TH17 cells is the orchestration of type 3 responses, in which neutrophils are the principal type of innate effector cell.


Immunology_Janeway

Immunology_Janeway. As discussed in Chapter 9, the development of TH17 cells is induced by the combined actions of TGF-β and the pro-inflammatory cytokines IL-6, IL-1, and IL-23 (see Fig. 9.31). The latter is preferentially produced by CD103+CD11b+ conventional dendritic cells that recognize MAMPs produced by extracellular bacteria, such as flagellin, which is recognized by TLR5; or MAMPs produced by fungi, such as β-glucan polymers of glucose expressed by yeast and fungi that are recognized by Dectin-1. As for TH1 and TH2 cells, the egress of TH17 cells from secondary lymphoid tissues is associated with altered chemokine expression: primarily the induction of CCR6, the ligand for which (CCL20) is produced by activated epithelial cells in mucosal tissues and skin, as well as TH17 cells themselves and ILC3 cells (see Figs. 11.8 and 11.9).


Immunology_Janeway

Immunology_Janeway. TH17 cells are stimulated to release IL-17A and IL-17F when they encounter antigen at sites of infection (Fig. 11.16). A primary effect of these cytokines is the enhanced production and recruitment of neutrophils. The receptor for TH17 IL-17 and IL-22 produced by TH17 cells induce the production of antimicrobial peptides by epithelial cells IL-17 IL-22 antimicrobial peptides IL-22 produced by TH17 increases epithelial cell turnover Increased epithelial cell division and shedding impairs bacterial colonization Direct killing or growth inhibition of bacteria attached to the epithelium turnover IL-22


Immunology_Janeway

Immunology_Janeway. Fig. 11.16 The immune response to extracellular bacteria produce cytokines that activate local epithelial and stromal cells to and some fungi is coordinated by activated TH17 cells. TH17 coordinate the immune response to extracellular bacteria and some cells activated by antigen-bearing macrophages and dendritic cells types of fungi. in barrier tissues (e.g., intestinal or respiratory mucosa, and skin) IL-17 produced by TH17 cells activates stromal cells and myeloid cells to produce G-CSF, which stimulates neutrophil production in bone marrow IL-17IL-17 G-CSF stromal cell myeloid cell bone marrow neutrophil production Increases numbers of circulating neutrophils to sustain supply of short-lived innate effectors at infection site


Immunology_Janeway

Immunology_Janeway. Increases numbers of circulating neutrophils to sustain supply of short-lived innate effectors at infection site Fig. 11.17 The cytokines IL-12 and IL-23 have a component in common, as do their receptors. The heterodimeric cytokines IL-12 and IL-23 both contain the p40 subunit, and the receptors for IL-12 and IL-23 have the IL-12Rβ1 subunit in common, which binds the p40 subunit. IL-12 signaling primarily activates the transcriptional activator STAT4, which increases IFN-γ production. IL-23 primarily activates STAT3, but also activates STAT4 weakly (not shown). Both cytokines augment the activity and proliferation of the CD4 subsets that express receptors for them; TH1 cells express IL-12R, and TH17 cells express primarily IL-23R, but can also express low levels of IL-12R (not shown). Mice deficient in p40 lack expression of both of these cytokines, and manifest immune defects as a result of deficiencies in both TH1 and TH17 activities.


Immunology_Janeway

Immunology_Janeway. IL-17A and IL-17F is expressed widely on cells such as fibroblasts, epithelial cells, and keratinocytes. IL-17 induces these cells to secrete various cytokines, including IL-6, which amplifies the TH17 response, and the hematopoietic factor granulocyte colony-stimulating factor (G-CSF), which increases the production of neutrophils by the bone marrow. IL-17 also stimulates production of the chemokines CXCL8 and CXCL2, the receptors for which (CXCR1 and CXCR2) are uniquely expressed by neutrophils (see Fig. 11.8). Thus, one important action of IL-17 at sites of infection is to induce local cells to secrete cytokines and chemokines that attract neutrophils.


Immunology_Janeway

Immunology_Janeway. TH17 cells also produce IL-22, a member of the IL-10 family that acts cooperatively with IL-17 to induce the expression by epithelial cells of antimicrobial proteins (see Fig. 11.16). These include β-defensins and the C-type lectins RegIIIβ and RegIIIγ, all of which can directly kill bacteria (see Section 2-4). IL-22 and IL-17 can also induce epithelial cells to produce metal-binding proteins that are bacteriostatic and fungistatic. Lipocalin-2 limits iron availability to bacterial pathogens; S100A8 and S100A9 are two antimicrobial peptides that heterodimerize to form the antimicrobial protein calprotectin, which sequesters zinc and manganese from microbes. Many of these antimicrobial agents are also produced by neutrophils recruited to the site of infection; calprotectin has been reported to comprise up to a third of the cytosolic protein of neutrophils. IL-22 also stimulates the proliferation and shedding of epithelial cells as a mechanism to deprive bacteria and fungi of a


Immunology_Janeway

Immunology_Janeway. reported to comprise up to a third of the cytosolic protein of neutrophils. IL-22 also stimulates the proliferation and shedding of epithelial cells as a mechanism to deprive bacteria and fungi of a ‘foothold’ for colonization at epithelial surfaces. While ILC3 cells in barrier tissues respond rapidly to pathogens to produce IL-22, pathogen-specific TH17 cells have been shown to amplify and sustain the production of IL-22 at sites of infection.


Immunology_Janeway

Immunology_Janeway. As in type 1 and type 2 responses, integration of innate and adaptive effector cells in the type 3 response is mediated in large part by the production of pathogen-specific antibodies that opsonize extracellular bacteria and fungi for destruction by neutrophils, macrophages, and complement. TFH cells that develop coordinately with TH17 cells promote the production of high-affinity IgG and IgA antibodies by plasma cells that can express CCR6 and thereby localize to sites of type 3 responses in barrier tissues, where they can arm neutrophils and macrophages ‘on-site.’ Antibodies are the principal immune reactants that clear primary infections by common extracellular bacteria that elicit type 3 responses, such as Staphylococcus aureus and Streptococcus pneumoniae. 11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions.


Immunology_Janeway

Immunology_Janeway. 11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions. The commitment of CD4 T cells to distinct lineages of effector cells occurs in peripheral lymphoid tissues, such as lymph nodes. However, the effector activities of these cells are not defined simply by the signals received in the lymphoid tissues. Evidence suggests that there is continuous regulation of the expansion and the effector activities of differentiated CD4 cells, in particular those of TH17 and TH1 cells, once they enter sites of infection.


Immunology_Janeway

Immunology_Janeway. As noted in Chapter 9, commitment of naive T cells to become TH17 cells is triggered by exposure to TGF-β and IL-6; commitment to become TH1 cells is initially triggered by IFN-γ. These initial conditions are not, however, sufficient to generate complete or effective TH17 or TH1 responses. In addition, each T-cell subset also requires stimulation by another cytokine: IL-23 in the case of TH17 cells, and IL-12 in the case of TH17 cells. IL-23 and IL-12 are closely related in structure; each is a heterodimer and they have a subunit in common (Fig. 11.17). IL-23 is composed of one p40 (IL-12 p40) and one p19 (IL-23 p19) subunit, whereas IL-12 has the p40 (IL-12 p40) subunit and a unique p35 (IL-12 p35) subunit. Committed TH17 cells express a receptor for IL-23, and, as will be discussed below, low levels of the receptor for IL-12. TH1 cells express the receptor for IL-12. The receptors for IL-12 and IL-23 are also related. They have a common subunit, IL-12Rβ1, which is expressed by naive


Immunology_Janeway

Immunology_Janeway. low levels of the receptor for IL-12. TH1 cells express the receptor for IL-12. The receptors for IL-12 and IL-23 are also related. They have a common subunit, IL-12Rβ1, which is expressed by naive T cells. Upon receipt of differentiating cytokine signals, developing TH17 cells synthesize IL-23R, the inducible component of the mature IL-23 receptor heterodimer;


Immunology_Janeway

Immunology_Janeway. TH1 cells from mice cured of infection with L. major are transferred into Rag2– or IL-12 p40–defcient mice, which are then injected with L. major TH1 cells synthesize IL-12Rβ2, the inducible component of the mature IL-12 receptor.


Immunology_Janeway

Immunology_Janeway. TH1 cells synthesize IL-12Rβ2, the inducible component of the mature IL-12 receptor. IL-23 and IL-12 amplify the activities of TH17 and TH1 cells, respectively. Like many other cytokines, they both act through the JAK–STAT intracellular signaling pathway (see Fig. 9.32). IL-23 signaling primarily activates the intracellular transcriptional activator STAT3, but also activates STAT4. In contrast, IL-12 strongly activates STAT4, with minimal activation of STAT3. IL-23 does not initiate the commitment of naive CD4 T cells to become TH17 cells, but it does stimulate their expansion and contributes to their maintenance. Many in vivo responses that depend on IL-17 are diminished in the absence of IL-23. For example, mice lacking the IL-23-specific subunit p19 show decreased production of IL-17A and IL-17F in the lung after infection by Klebsiella pneumoniae.


Immunology_Janeway

Immunology_Janeway. IL-12 regulates the effector activity of committed TH1 cells at sites of infection. Studies of two different pathogens have shown that the initial differentiation of TH1 cells is not sufficient for protection, and that continuous signals are required. Mice deficient in IL-12 p40 can resist initial infection by Toxoplasma gondii as long as IL-12 is administered continuously. If IL-12 is administered during the first 2 weeks of infection, p40-deficient mice survive the initial infection and establish a latent chronic infection characterized by cysts containing the pathogen. When IL-12 administration is stopped, however, these mice gradually reactivate the latent cysts and the animals eventually die of toxoplasmic encephalitis. IFN-γ production by pathogen-specific T cells decreases in the absence of IL-12 but can be restored by IL-12 administration. Similarly, the adoptive transfer of differentiated TH1 cells from mice cured of Leishmania major protects RAG-deficient mice infected by L.


Immunology_Janeway

Immunology_Janeway. of IL-12 but can be restored by IL-12 administration. Similarly, the adoptive transfer of differentiated TH1 cells from mice cured of Leishmania major protects RAG-deficient mice infected by L. major, but cannot protect IL-12 p40-deficient mice (Fig. 11.18). Together, these experiments indicate that TH1 cells continue to respond to signals during an infection, and that continuous IL-12 is needed to sustain the effectiveness of differentiated TH1 cells against at least some pathogens.


Immunology_Janeway

Immunology_Janeway. 11-12 Effector T cells can be activated to release cytokines independently of antigen recognition.


Immunology_Janeway

Immunology_Janeway. As we have seen, a central paradigm in adaptive immunity is the requirement for antigen recognition by the cognate receptors of naive lymphocytes to induce their differentiation into mature effector cells. However, effector T cells also acquire the ability to be activated by pairs of cytokines, independently of antigen recognition by their T-cell receptor. The cytokine pairs that mediate this ‘noncognate’ function of differentiated effector cells appear to be the same as those that activate the ILC subset that parallels each T-cell subset (Fig. 11.19). And in each case, the pair of stimulating cytokines includes one cytokine that activates a receptor that signals via a STAT factor, and one that activates a receptor that signals via NFκB—typically a member of the IL-1 receptor family. Thus, for both TH1 cells and ILC1 cells, stimulation by IL-12 (STAT4) plus IL-18 induces production of IFN-γ. Similarly, stimulation of TH2 and ILC2 cells by TSLP (STAT5) plus IL-33 produces IL-5 and


Immunology_Janeway

Immunology_Janeway. Thus, for both TH1 cells and ILC1 cells, stimulation by IL-12 (STAT4) plus IL-18 induces production of IFN-γ. Similarly, stimulation of TH2 and ILC2 cells by TSLP (STAT5) plus IL-33 produces IL-5 and IL-13, and both TH17 and ILC3 cells stimulated by IL-23 (STAT3) plus IL-1 produce IL-17 and IL-22. In this way, mature effector CD4 T cells acquire innate-like functional properties that allow them to amplify different types of immune responses without the requirement for antigen recognition. Note that in the case of type 1 and type 3 cells, the IL-1 family member involved (IL-18 and IL-1, respectively) is produced by inflammasome activation in myeloid cells. Conversely, IL-33,


Immunology_Janeway

Immunology_Janeway. TH1 cells protect Rag2-defcient mice, but mice lacking the IL-12 p40 subunit show progressive growth of the parasite Fig. 11.18 Continuous IL-12 is necessary for resistance to pathogens requiring TH1 responses. Mice that have eliminated an infection with Leishmania major and have generated TH1 cells specific to the pathogen were used as a source of T cells that were adoptively transferred either into Rag2-deficient mice, which lack T cells and B cells and cannot control L. major infection but can produce IL-12, or into mice lacking IL-12 p40, which cannot produce IL-12. On subsequent infection of the Rag2-deficient mice, lesions did not enlarge because the transferred TH1 cells conferred immunity. But despite the fact that the transferred cells were already differentiated TH1 cells, they did not confer resistance to IL-12 p40-deficient mice, which lacked a source of IL-12 to support TH1 function.


Immunology_Janeway

Immunology_Janeway. Fig. 11.19 Effector T cells can be activated to release cytokines independently of antigen recognition. Analogous to ILCs, effector T cells can be stimulated to produce effector cytokines independently of T-cell receptor signaling via the coordinate actions of pairs of cytokines. which activates type 2 responses, is inactivated by the inflammasome, indicating another basis for counterregulation between type 2 and type 1 or type 3 immune responses. Although the precise role of noncognate activation of effector T cells by cytokines is not clearly defined, it may provide a mechanism by which tissue-resident memory T cells could be rapidly recruited in recall, or memory, responses (see Section 11-22). 11-13 Effector T cells demonstrate plasticity and cooperativity that enable adaptation during anti-pathogen responses.


Immunology_Janeway

Immunology_Janeway. Thus far we have discussed subsets of effector CD4 T cells as though they are intrinsically stable, such that their functional phenotype is unchanging after their development. Similarly, we have discussed the different types of immunity as though they are unimodal, that is, only one type of response is recruited to clear a given pathogen. Although this is often the case, it is not always so. Just as the pathogens can modify their tactics to evade destruction, so too can the elicited effector T cells adapt in order to clear the host of these pathogens. Adaptation can occur by flexibility in the programming of individual T cells, referred to as T-cell plasticity, wherein effector T cells can transition into different cytokine phenotypes contingent on changes in the local inflammatory environment. It can also occur as a result of cooperation between different subsets of T cells. Plasticity applies to cells of the same clonal origin and identical antigenic specificity, whereas cooperation


Immunology_Janeway

Immunology_Janeway. It can also occur as a result of cooperation between different subsets of T cells. Plasticity applies to cells of the same clonal origin and identical antigenic specificity, whereas cooperation applies to cells that develop from different clonal precursors and target different antigens, typically at different stages of an infection.


Immunology_Janeway

Immunology_Janeway. Although some degree of plasticity has been experimentally demonstrated for each of the major effector CD4 subsets, it appears to be most prevalent in type 3 responses. It is common for TH17 cells to deviate, or be ‘reprogrammed,’ into TH1-type cells (Fig. 11.20). This was originally discovered using cytokine reporter mice, in which TH17 cells that express IL-17F could be identified and isolated based on their expression of a cell-associated reporter molecule controlled by the Il17f gene. When TH17 cells isolated using the reporter were restimulated in the presence of the TH1-polarizing cytokine IL-12, their progeny rapidly lost expression of IL-17 and acquired expression of IFN-γ. Moreover, repetitive restimulation of TH17 cells with the TH17 lineage cytokine IL-23 could lead to a subset of progeny that also acquired features of TH1 cells. In both cases, reprogramming of TH17 cells into TH1 cells required expression of the TH1-associated transcription factor T-bet and loss of the


Immunology_Janeway

Immunology_Janeway. of progeny that also acquired features of TH1 cells. In both cases, reprogramming of TH17 cells into TH1 cells required expression of the TH1-associated transcription factor T-bet and loss of the TH17-associated transcription factor RORγt, both of which were contingent on activation of STAT4 by the IL-12 and IL-23 receptors. Thus, TH17 cells deficient for either T-bet or STAT4 failed to demonstrate transition into TH1 cells, or ‘TH17 cell plasticity.’


Immunology_Janeway

Immunology_Janeway. An example of the importance of effector T-cell plasticity and cooperativity between subsets is found in host protection against facultative intracellular bacterial pathogens, such as Salmonella, which, unlike obligate extracellular bacteria, have also evolved mechanisms to survive within macrophages that are not activated by IFN-γ. Early in infection, Salmonella can colonize the intestinal epithelium similarly to other enteric Gram-negative pathogens. During this period, a TH17 response dominates, resulting in a robust IL-17induced influx of neutrophils that engulf extracellular bacteria and IL-22induced release of antimicrobial proteins that restrain bacterial growth in the intestinal lumen. During this intestinal phase of infection, much of the T-cell response appears to be directed against antigenic epitopes within bacterial flagellins, which are potent activators of TLR5. Activation of this innate sensor promotes IL-23 expression by CD11b+ classical dendritic cells in the


Immunology_Janeway

Immunology_Janeway. against antigenic epitopes within bacterial flagellins, which are potent activators of TLR5. Activation of this innate sensor promotes IL-23 expression by CD11b+ classical dendritic cells in the intestine, and thereby induces a type 3 immune response. Flagellin-specific TH1cells also emerge during the early intestinal phase of infection, and may arise from TH17 cell precursors as a result of plasticity. To escape destruction by macrophages activated for intracellular killing by these ‘ex-TH17’ TH1 cells, Salmonella simultaneously downregulates the expression of flagellin and begins synthesizing new proteins, such as SseI and SseJ, that allow it to suppress intracellular killing within macrophages. This allows Salmonella to both evade detection by flagellin-specific T cells and use the host macrophage as a safe haven to shield it from extracellular killing—at least temporarily—as the infection spreads systemically.