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Immunology_Janeway. Goins, C.L., Chappell, C.P., Shashidharamurthy, R., Selvaraj, P., and Jacob, J.: Immune complex-mediated enhancement of secondary antibody responses. J. Immunol. 2010, 184:6293–6298. Kaji, T., Furukawa, K., Ishige, A., Toyokura, I., Nomura, M., Okada, M., Takahashi, Y., Shimoda, M., and Takemori, T.: Both mutated and unmutated memory B cells accumulate mutations in the course of the secondary response and develop a new antibody repertoire optimally adapted to the secondary stimulus. Int. Immunol. 2013, 25:683–695. 11-20 MHC tetramers identify memory T cells that persist at an increased in frequency relative to their frequency as naive T cells. Hataye, J., Moon, J.J., Khoruts, A., Reilly, C., and Jenkins, M.K.: Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 2006, 312:114–116.


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Immunology_Janeway. Hataye, J., Moon, J.J., Khoruts, A., Reilly, C., and Jenkins, M.K.: Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 2006, 312:114–116. Pagán, A.J., Pepper, M., Chu, H.H., Green, J.M., and Jenkins, M.K.: CD28 promotes CD4+ T cell clonal expansion during infection independently of its YMNM and PYAP motifs. J. Immunol. 2012, 189:2909–2917. Pepper, M., Pagán, A.J., Igyártó, B.Z., Taylor, J.J., and Jenkins, M.K.: Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 2011, 35:583–595. 11-21 Memory T cells arise from effector T cells that maintain sensitivity to IL-7 or IL-15. Akondy, R.S., Monson, N.D., Miller, J.D., Edupuganti, S., Teuwen, D., Wu, H., Quyyumi, F., Garg, S., Altman, J.D., Del Rio, C., et al.: The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 2009, 183:7919–7930.


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Immunology_Janeway. Bradley, L.M., Atkins, G.G., and Swain, S.L.: Long-term CD4+ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J. Immunol. 1992, 148:324–331. Kaech, S.M., Hemby, S., Kersh, E., and Ahmed, R.: Molecular and functional profiling of memory CD8 T cell differentiation. Cell 2002, 111:837–851. Kassiotis, G., Garcia, S., Simpson, E., and Stockinger, B.: Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nat. Immunol. 2002, 3:244–250. Ku, C.C., Murakami, M., Sakamoto, A., Kappler, J., and Marrack, P.: Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 2000, 288:675–678. Rogers, P.R., Dubey, C., and Swain, S.L.: Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J. Immunol. 2000, 164:2338–2346.


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Immunology_Janeway. Rogers, P.R., Dubey, C., and Swain, S.L.: Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J. Immunol. 2000, 164:2338–2346. Wherry, E.J., Teichgraber, V., Becker, T.C., Masopust, D., Kaech, S.M., Antia, R., von Andrian, U.H., and Ahmed, R.: Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 2003, 4:225–234. 11-22 Memory T cells are heterogeneous and include central memory, effector memory, and tissue-resident subsets. Cerottini, J.C., Budd, R.C., and MacDonald, H.R.: Phenotypic identification of memory cytolytic T lymphocytes in a subset of Lyt-2+ cells. Ann. N. Y. Acad. Sci. 1988, 532:68–75. Kaech, S.M., Tan, J.T., Wherry, E.J., Konieczny, B.T., Surh, C.D., and Ahmed, R.: Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 2003, 4:1191–1198.


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Immunology_Janeway. Lanzavecchia, A., and Sallusto, F.: Understanding the generation and function of memory T cell subsets. Curr. Opin. Immunol. 2005, 17:326–332. Mueller, S.N., Gebhardt, T., Carbone, F.R., and Heath, W.R.: Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 2012, 31:137–161. Sallusto, F., Geginat, J., and Lanzavecchia, A.: Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 2004, 22:745–763. Sallusto, F., Lenig, D., Forster, R., Lipp, M., and Lanzavecchia, A.: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999, 401:708–712. Skon, C.N., Lee, J.Y., Anderson, K.G., Masopust, D., Hogquist, K.A., and Jameson, S.C.: Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 2013, 14:1285–1293.


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Immunology_Janeway. 11-23 CD4 T-cell help is required for CD8 T-cell memory and involves CD40 and IL-2 signaling. Bourgeois, C., and Tanchot, C.: CD4 T cells are required for CD8 T cell memory generation. Eur. J. Immunol. 2003, 33:3225–3231. Bourgeois, C., Rocha, B., and Tanchot, C.: A role for CD40 expression on CD8 T cells in the generation of CD8 T cell memory. Science 2002, 297:2060–2063. Janssen, E.M., Lemmens, E.E., Wolfe, T., Christen, U., von Herrath, M.G., and Schoenberger, S.P.: CD4 T cells are required for secondary expansion and memory in CD8 T lymphocytes. Nature 2003, 421:852–856. Shedlock, D.J., and Shen, H.: Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003, 300:337–339. Sun, J.C., Williams, M.A., and Bevan, M.J.: CD4 T cells are required for the maintenance, not programming, of memory CD8 T cells after acute infection. Nat. Immunol. 2004, 5:927–933.


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Immunology_Janeway. Sun, J.C., Williams, M.A., and Bevan, M.J.: CD4 T cells are required for the maintenance, not programming, of memory CD8 T cells after acute infection. Nat. Immunol. 2004, 5:927–933. Tanchot, C., and Rocha, B.: CD8 and B cell memory: same strategy, same signals. Nat. Immunol. 2003, 4:431–432. Williams, M.A., Tyznik, A.J., and Bevan, M.J.: Interleukin-2 signals during priming are required for secondary expansion of CD8 memory T cells. Nature 2006, 441:890–893. 11-24 In immune individuals, secondary and subsequent responses are mainly attributable to memory lymphocytes. Fazekas de St Groth, B., and Webster, R.G.: Disquisitions on original antigenic sin. I. Evidence in man. J. Exp. Med. 1966, 140:2893–2898. Fridman, W.H.: Regulation of B cell activation and antigen presentation by Fc receptors. Curr. Opin. Immunol. 1993, 5:355–360.


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Immunology_Janeway. Fridman, W.H.: Regulation of B cell activation and antigen presentation by Fc receptors. Curr. Opin. Immunol. 1993, 5:355–360. Klenerman, P., and Zinkernagel, R.M.: Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 1998, 394:482–485. Mongkolsapaya, J., Dejnirattisai, W., Xu, X.N., Vasanawathana, S., Tangthawornchaikul, N., Chairunsri, A., Sawasdivorn, S., Duangchinda, T., Dong, T., Rowland-Jones, S., et al.: Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 2003, 9:921–927. Pollack, W., Gorman, J.G., Freda, V.J., Ascari, W.Q., Allen, A.E., and Baker, W.J.: Results of clinical trials of RhoGAm in women. Transfusion 1968, 8:151–153. Zehn, D., Turner, M.J., Lefrançois, L., and Bevan, M.J.: Lack of original antigenic sin in recall CD8+ T cell responses. J. Immunol. 2010, 184:6320–6326. The Mucosal Immune System


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Immunology_Janeway. Zehn, D., Turner, M.J., Lefrançois, L., and Bevan, M.J.: Lack of original antigenic sin in recall CD8+ T cell responses. J. Immunol. 2010, 184:6320–6326. The Mucosal Immune System Adaptive immune responses are typically initiated in the peripheral lymph nodes that drain the infected tissues. While most internal tissues are free of active microbial growth, the skin and the various mucosae lining organs that directly contact the external world will have continuous encounters with environmental microbes. These surfaces are where most pathogens invade. In this chapter, we will discuss the specialized features of the immune system that serves these mucosal surfaces—the mucosal immune system.


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Immunology_Janeway. The mucosal immune system, in particular, that of the gut, may well have been the first part of the vertebrate adaptive immune system to evolve, possibly linked to the need to deal with the vast populations of commensal bacteria that coevolved with the vertebrates. Organized lymphoid tissues and immunoglobulin antibodies are first found in vertebrates in the gut of primitive cartilaginous fishes, and two important central lymphoid organs—the thymus and the avian bursa of Fabricius—derive from the embryonic intestine. Fish also have a primitive form of secretory antibody that protects their body surface and may be the forerunner of IgA in mammals. It has therefore been suggested that the mucosal immune system represents the original vertebrate immune system, and that the spleen and lymph nodes are later specializations The nature and structure of the mucosal immune system.


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Immunology_Janeway. The first line of defense against invasion by potential pathogens and commensal microorganisms is the thin layer of epithelium that covers all these surfaces. However, the epithelium can be breached relatively easily, and so its barrier function needs to be supplemented by defenses provided by the cells and molecules of the mucosal immune system. The innate defenses of mucosal tissues, such as antimicrobial peptides and cells bearing invariant pathogen-recognition receptors, are described in Chapters 2 and 3. In this chapter we concentrate on the adaptive mucosal immune system, highlighting only those innate responses that are of particular importance to our discussion. Many of the anatomical and immunological principles underlying the mucosal immune system apply to all its constituent tissues; here we will use the intestine as our example, and the reader is referred to the general references at the end of this chapter for further details of the other sites.


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Immunology_Janeway. 12-1 The mucosal immune system protects the internal surfaces of the body. The mucosal immune system comprises the internal body surfaces that are lined by a mucus-secreting epithelium—the gastrointestinal tract, the upper and lower respiratory tract, the urogenital tract, and the middle ear. It also includes the exocrine glands associated with these organs, such as the conjunctivae and lacrymal glands of the eye, the salivary glands, and the lactating breast (Fig. 12.1). The mucosal surfaces represent an enormous area to The nature and structure of the mucosal immune system. The mucosal response to infection and regulation of mucosal immune responses.


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Immunology_Janeway. The nature and structure of the mucosal immune system. The mucosal response to infection and regulation of mucosal immune responses. respiratory tract gastrointestinal tract urogenital tract conjunctiva esophagus stomach intestine sinus middle ear trachea lungs oral cavity lachrymal gland salivary gland Mucosal tissues of the human body mammary gland kidney uterus bladder vagina Fig. 12.1 The mucosal immune system. The tissues of the mucosal immune system are the lymphoid organs and cells associated with the intestine, respiratory tract, and urogenital tract, as well as the oral cavity, pharynx, middle ear, and the glands associated with these tissues, such as the salivary glands and lachrymal glands. The lactating breast is also part of the mucosal immune system. be protected. The human small intestine, for instance, has a surface area of almost 400 m2, which is 200 times that of the skin.


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Immunology_Janeway. be protected. The human small intestine, for instance, has a surface area of almost 400 m2, which is 200 times that of the skin. The mucosal immune system forms the largest part of the body’s immune tissues, containing approximately three-quarters of all lymphocytes and producing the majority of immunoglobulin in healthy individuals. It is also exposed continuously to antigens and other materials entering from the environment. When compared with lymph nodes and spleen (which in this chapter we will call the systemic immune system), the mucosal immune system has many unique and unusual features (Fig. 12.2).


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Immunology_Janeway. Fig. 12.2 Distinctive features of the mucosal immune system. The mucosal immune system is bigger, encounters a wider range of antigens, and encounters them much more frequently than the rest of the immune system—what we call in this chapter the systemic immune system. This is reflected in distinctive anatomical features, specialized mechanisms for the uptake of antigen, and unusual effector and regulatory responses that are designed to prevent unwanted immune responses to food and other innocuous antigens. The nature and structure of the mucosal immune system. Worldwide deaths annually from mucosal infections Acute respiratory infections (4 million) Diarrheal diseases (2.2 million) Tuberculosis (1.5 million) HIV/AIDS (2 million) Measles (400,000) Hepatitis B (103,000*) Whooping cough (294,000) Roundworm and hookworm (6000) 0 4 million3 million2 million1 million


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Immunology_Janeway. Because of their physiological functions in gas exchange (the lungs), food absorption (the gut), sensory activities (eyes, nose, mouth, and throat), and reproduction (uterus and vagina), the mucosal surfaces are thin and permeable barriers to the interior of the body. The importance of these tissues to life means that effective defense mechanisms are essential to protect them from invasion. Equally significant is that their fragility and permeability create obvious vulnerability to infection, and it is not surprising that the vast majority of infectious agents invade the human body by these routes (Fig. 12.3). Diarrheal diseases, acute respiratory infections, pulmonary tuberculosis, measles, whooping cough, and worm infestations continue to be the major causes of death throughout the world, especially in infants in developing countries. To these must be added the human immunodeficiency virus (HIV), a pathogen whose natural route of entry via a mucosal surface is often overlooked, as


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Immunology_Janeway. especially in infants in developing countries. To these must be added the human immunodeficiency virus (HIV), a pathogen whose natural route of entry via a mucosal surface is often overlooked, as well as other sexually transmitted infections such as syphilis.


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Immunology_Janeway. The mucosal surfaces are also portals of entry for a vast array of foreign antigens that are not pathogenic. This is best seen in the gut, which is exposed to enormous quantities of food proteins—an estimated 30–35 kg per year per person. At the same time, the healthy large intestine is colonized by at least a thousand species of bacteria that live in symbiosis with their host and are known as commensal microorganisms, or the microbiota. These bacteria are present at levels of at least 1012 organisms per milliliter in the colon contents, making them the most numerous cells in the body by a factor of 10. Substantial populations of viruses and fungi are also found in the healthy intestine. In normal circumstances these organisms do no harm, and many are beneficial to their hosts, having important metabolic functions, as well as being essential for normal immune function. The other mucosal surfaces are also colonized by substantial populations of resident commensal organisms (Fig. 12.4).


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Immunology_Janeway. As food proteins and the microbiota contain many foreign antigens, they are capable of being recognized by the adaptive immune system. Generating protective immune responses against these harmless agents would, however, be inappropriate and wasteful. Indeed, aberrant immune responses of this kind are now believed to be the cause of some relatively common diseases, including celiac disease (caused by a response to the wheat protein gluten; discussed in Chapter 14) and inflammatory bowel diseases such as Crohn’s disease (a response to commensal bacteria). As we shall see, the intestinal mucosal immune system has evolved means of distinguishing harmful pathogens from antigens in food and the normal microbiota. Similar issues are faced at other mucosal surfaces, such as the respiratory tract and female genital


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Immunology_Janeway. Fig. 12.3 Mucosal infections comprise one of the biggest health problems worldwide. Most of the pathogens that cause death throughout the world either are those of mucosal surfaces or enter the body through these routes. Respiratory infections are caused by numerous bacteria (such as Streptococcus pneumoniae and Haemophilus influenzae, which cause pneumonia; and Bordetella pertussis, the cause of whooping cough) and viruses (such as influenza and respiratory syncytial virus). Diarrheal diseases are caused by both bacteria (such as the cholera bacterium Cholera vibrio) and viruses (such as rotaviruses). The human immunodeficiency virus (HIV) that causes AIDS enters through the mucosa of the urogenital tract or is secreted into breast milk and passed from mother to child in this way. The bacterium Mycobacterium tuberculosis, which causes tuberculosis, also enters through the respiratory tract. Measles manifests itself as a systemic disease, but it originally enters via the oral/


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Immunology_Janeway. The bacterium Mycobacterium tuberculosis, which causes tuberculosis, also enters through the respiratory tract. Measles manifests itself as a systemic disease, but it originally enters via the oral/ respiratory route. Hepatitis B is also a sexually transmitted virus. Finally, parasitic worms inhabiting the intestine cause chronic debilitating disease and premature death. Most of these deaths, especially those from acute respiratory and diarrheal diseases, occur in children under 5 years old in the developing world, and there are still no effective vaccines against many of these pathogens. Numbers shown are the most recent estimated figures available (The Global Burden of Disease: 2004 Update. World Health Organization, 2008). *Does not include deaths from liver cancer or cirrhosis resulting from chronic infection.


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PC2 (4.4%)

Immunology_Janeway. PC2 (4.4%)


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Immunology_Janeway. Fig. 12.4Composition of the commensal microbiota at (Actinobacteria), Bacteroides fragilis (Bacteroidetes), and Escherichia different mucosal surfaces in healthy humans. Panel a: coli (Proteobacteria). Panel b: principal component analysis of the the different sizes of the pie charts for different sites reflect the microbiomes isolated from the indicated human tissues, plotting number of distinct bacterial species typically present at those the first and second principal components. The primary component sites. The colon contains the greatest number of different species of microbiome variation is due to body area and accounts for (over 1000 as estimated from individual surveys). The color key 13% of the variation in microbial identity between samples taken indicates the four bacterial phyla that contain the majority of from these sites. a, adapted from Dethlefsen, L., et al.: Nature commensal species. Ubiquitous commensal bacteria include 2007, 449:811‑818. b, from Huttenhower, C., et


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Immunology_Janeway. that contain the majority of from these sites. a, adapted from Dethlefsen, L., et al.: Nature commensal species. Ubiquitous commensal bacteria include 2007, 449:811‑818. b, from Huttenhower, C., et al.: Nature 2012, Lactobacillus and Clostridium spp. (Firmicutes), Bifidobacterium spp. 486:207–214.


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Immunology_Janeway. tract. Here, protective immunity against pathogens is essential, but many of the antigens entering these tissues are also harmless, being derived from commensal organisms, pollen, other innocuous environmental material, and, in the lower urogenital tract, seminal fluid. The fetus is a further important source of foreign antigen encountered by the normal mucosal immune system to which immune responses must be controlled. 12-2 Cells of the mucosal immune system are located both in anatomically defined compartments and scattered throughout mucosal tissues.


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Immunology_Janeway. 12-2 Cells of the mucosal immune system are located both in anatomically defined compartments and scattered throughout mucosal tissues. Lymphocytes and other immune-system cells such as macrophages and dendritic cells are found throughout the intestinal tract, both in organized tissues and scattered throughout the surface epithelium of the mucosa and in the underlying layer of connective tissue called the lamina propria. The organized secondary lymphoid tissues in the gut comprise a group of organs known as the gut-associated lymphoid tissues (GALT), together with the draining mesenteric and caudal lymph nodes (Fig. 12.5). The GALT and the mesenteric lymph nodes have the anatomically compartmentalized structure typical of peripheral lymphoid organs, and are sites at which immune responses are initiated. The cells scattered throughout the epithelium and the lamina propria comprise the effector cells of the local immune response.


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Immunology_Janeway. The intestinal mucosa of the small intestine to mesenteric lymph node isolated lymphoid follicle Intestinal lumen Peyer’s patch subepithelial dome crypt follicle (B cells) T-cell area lamina propria lamina propria lymphocyte epithelium intraepithelial lymphocyte lymphatic villus Scattered lymphoid cells Organized lymphoid tissues Intestinal lymphocytes are found in organized tissues where immune responses are induced, and scattered throughout the intestine, where they carry out effector functions Fig. 12.5 Gut-associated lymphoid tissues and lymphocyte populations.


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Immunology_Janeway. is made up of fingerlike processes (villi) covered by a thin layer of epithelial cells (red) that are responsible for digestion of food and absorption of nutrients. These epithelial cells are replaced continually by new cells that derive from stem cells in the crypts. The tissue layer underlying the epithelium is called the lamina propria, and is colored pale yellow throughout this chapter. Lymphocytes are found in several discrete compartments in the intestine, with the organized lymphoid tissues such as Peyer’s patches and isolated lymphoid follicles forming what is known as the gut‑associated lymphoid tissues (GALT). These tissues lie in the wall of the intestine itself, separated from the contents of the intestinal lumen by the single layer of epithelium. The draining lymph nodes for the gut are the mesenteric lymph nodes, which are connected to Peyer’s patches and the intestinal mucosa by afferent lymphatic vessels and are the largest lymph nodes in the body. Together, these


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Immunology_Janeway. for the gut are the mesenteric lymph nodes, which are connected to Peyer’s patches and the intestinal mucosa by afferent lymphatic vessels and are the largest lymph nodes in the body. Together, these organized tissues are the sites of antigen presentation to T cells and B cells and are responsible for the induction phase of immune responses. Peyer’s patches and mesenteric lymph nodes contain discrete T‑cell areas (blue) and B‑cell follicles (yellow), while the isolated follicles comprise mainly B cells. Many lymphocytes are found scattered throughout the mucosa outside the organized lymphoid tissues: these are effector cells—effector T cells and antibody‑secreting plasma cells, as well as innate lymphoid cells (ILCs). Effector lymphocytes are found both in the epithelium and in the lamina propria. Lymphatics also drain from the lamina propria to the mesenteric lymph nodes.


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Immunology_Janeway. The GALT comprises the Peyer’s patches, which are present only in the small intestine; isolated lymphoid follicles (ILF), which are found throughout the intestine; the appendix (in humans); and the tonsils and adenoids in the throat. The palatine tonsils, adenoids, and lingual tonsils are large aggregates of lymphoid tissue covered by a layer of squamous epithelium and form a ring, known as Waldeyer’s ring, at the back of the mouth around the entrance of the gut and airways (Fig. 12.6). They often become extremely enlarged in childhood because of recurrent infections, and in the past were frequently removed as a result. A reduced IgA response to oral polio vaccination has been seen in individuals who have had their tonsils and adenoids removed. The tonsils and adenoids form a ring of lymphoid tissues, Waldeyer’s ring, around the entrance of the gut and airway adenoid palatine tonsil lingual tonsil tongue


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Immunology_Janeway. The tonsils and adenoids form a ring of lymphoid tissues, Waldeyer’s ring, around the entrance of the gut and airway adenoid palatine tonsil lingual tonsil tongue Fig. 12.6 A ring of lymphoid organs called Waldeyer’s ring surrounds the entrance to the intestine and respiratory tract. The adenoids lie at either side of the base of the nose, while the palatine tonsils lie at either side of the back of the oral cavity. The lingual tonsils are discrete lymphoid organs on the base of the tongue. The micrograph shows a section through an inflamed human tonsil, where the areas of organized lymphoid tissue are covered by a layer of squamous epithelium (at top of photo). The surface contains deep crevices (crypts) that increase the surface area but can easily become sites of infection. Hematoxylin and eosin staining. Magnification ×100. Fig. 12.7 Transport of antigens by M cells facilitates antigen presentation.


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Immunology_Janeway. The first panel illustrates the passage of antigen through M cells in the follicle‑associated epithelium of Peyer’s patches. M cells have convoluted basal membranes that form ‘pockets’ within the epithelial layer, allowing close contact with lymphocytes and other cells. This favors the local transport of antigens that have been taken up from the intestine by the M cells and their delivery to dendritic cells for antigen presentation. The top right micrograph of a Peyer’s patch stained with fluorescently labeled antibodies shows epithelial cells (cytokeratin, dark blue), with M‑cell pockets inferred from the presence of T cells (CD3, red) and B cells (CD20, green). At bottom right, Peyer’s patch follicle epithelium shows CX3CR1expressing myeloid cells (green), which include some dendritic cells, interacting with M cells identified by expression of peptidoglycan recognition protein‑S (red) and apical staining for the UEA‑1 lectin (cyan). Some CX3CR1‑expressing cells extend processes into


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Immunology_Janeway. interacting with M cells identified by expression of peptidoglycan recognition protein‑S (red) and apical staining for the UEA‑1 lectin (cyan). Some CX3CR1‑expressing cells extend processes into the M cells (arrows). Top right, micrograph from Espen, S., et al.: Immunol. Today 1999, 20:141–151. Bottom right, micrograph from Wang et al.: J. Immunol. 2011, 187:5277–5285.


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Immunology_Janeway. The Peyer’s patches of the small intestine, the lymphoid tissue of the appendix, and the isolated lymphoid follicles are located within the intestinal wall. Peyer’s patches are important sites for the initiation of immune responses in the gut. Visible to the naked eye, they have a distinctive appearance, forming dome-like aggregates of lymphoid cells that project into the intestinal lumen (see Fig. 1.24). There are 100–200 Peyer’s patches in the human small intestine. They are much richer in B cells than the systemic peripheral lymphoid organs, each Peyer’s patch consisting of a large number of B-cell follicles with germinal centers, with small T-cell areas between and immediately below the follicles (see Fig. 12.5). The subepithelial dome area lies immediately beneath the epithelium and is rich in dendritic cells, T cells, and B cells. Separating the lymphoid tissues from the gut lumen is a layer of follicle-associated epithelium. This contains conventional intestinal epithelial


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Immunology_Janeway. and is rich in dendritic cells, T cells, and B cells. Separating the lymphoid tissues from the gut lumen is a layer of follicle-associated epithelium. This contains conventional intestinal epithelial cells known as enterocytes and a smaller number of specialized epithelial cells called microfold cells (M cells), as shown in Fig. 1.24. M-cell development is controlled by local B cells and RANK ligand (RANKL), which is a member of the tumor necrosis factor (TNF) superfamily like CD40L (see Section 7-23). Unlike the enterocytes that make up most of the intestinal epithelium, M cells have a folded luminal surface instead of microvilli and do not secrete digestive enzymes or mucins, and so lack the thick layer of surface mucus (the glycocalyx) found covering conventional epithelial cells (see Fig. 1.24). They are therefore directly exposed to microorganisms and particles within the gut lumen and are the preferred route by which antigens such as microbes enter the Peyer’s patch from the


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Immunology_Janeway. Fig. 1.24). They are therefore directly exposed to microorganisms and particles within the gut lumen and are the preferred route by which antigens such as microbes enter the Peyer’s patch from the lumen (Fig. 12.7). The follicle-associated epithelium also contains lymphocytes and dendritic cells.


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Immunology_Janeway. Several thousand isolated lymphoid follicles can be identified microscopically throughout the small and large intestines, but they are more frequent in the large intestine, correlating with the load of local microorganisms. Like Peyer’s patches, these follicles have an epithelium containing M cells that lies over the organized lymphoid tissue. However, they contain mainly B cells and develop only after birth in response to antigen stimulation due to colonization of the gut by commensal microorganisms. Peyer’s patches, in contrast, are already present in the fetal gut, although their full development is not completed until after birth. In the mouse gut, isolated lymphoid follicles seem to arise from small aggregates in the intestinal wall called cryptopatches, which contain dendritic cells and lymphoid tissue inducer (LTi) cells (see Section 9-2). Cryptopatches have not yet been identified in the human gut. Peyer’s patches and isolated lymphoid follicles are connected by lymphatics to


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Immunology_Janeway. and lymphoid tissue inducer (LTi) cells (see Section 9-2). Cryptopatches have not yet been identified in the human gut. Peyer’s patches and isolated lymphoid follicles are connected by lymphatics to the draining lymph nodes.


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Immunology_Janeway. The tissues of the small intestine drain to the mesenteric lymph nodes, which are located in the connective tissue that tethers the intestine to the rear wall of the abdomen. These are the largest lymph nodes in the body and play a crucial role in initiating and shaping immune responses to intestinal antigens. The mucosal surface and lymphoid aggregates of the large intestine drain to part of the mesenteric lymph node and to a separate node known as the caudal lymph node, found close to the bifurcation of the aorta. The mesenteric lymph nodes and Peyer’s patches differentiate independently of the systemic immune system during fetal development, and their development involves distinct chemokines and receptors of the tumor necrosis factor (TNF) family (see Section 9-2). The differences between the GALT and the systemic lymphoid organs are thus imprinted early in life.


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Immunology_Janeway. In some species such as mice, isolated lymphoid follicles are also found in the lining of the nose, and in the wall of the upper respiratory tract; those in the nose are called nasal-associated lymphoid tissues (NALT), while those in the upper respiratory tract are known as bronchus-associated lymphoid tissues (BALT). The term mucosa-associated lymphoid tissues (MALT) is sometimes used to refer collectively to all such tissues found in mucosal organs, although defined organized lymphoid tissues are not found in the nose or respiratory tract in adult humans unless infection is present. 12-3 The intestine has distinctive routes and mechanisms of antigen uptake.


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Immunology_Janeway. Antigens present at mucosal surfaces must be transported across an epithelial barrier before they can stimulate the mucosal immune system. Peyer’s patches and isolated lymphoid follicles are highly adapted for the uptake of antigen from the intestinal lumen. The M cells in the follicle-associated epithelium are continually taking up molecules and particles from the gut lumen by endocytosis or phagocytosis (see Fig. 12.7). For several bacteria this may involve specific recognition of the bacterial FimH protein found in type 1 pili by a glycoprotein (GP2) on the M cell. This material is transported through the interior of the cell in membrane-bound vesicles to the basal cell membrane, where it is released into the extracellular space—a process known as transcytosis. Because M cells lack a glycocalyx and so are much more accessible than enterocytes, a number of pathogens target M cells to gain access to the subepithelial space, even though they then find themselves in the heart of the


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Immunology_Janeway. glycocalyx and so are much more accessible than enterocytes, a number of pathogens target M cells to gain access to the subepithelial space, even though they then find themselves in the heart of the intestinal adaptive immune system. These include Salmonella enterica serotype Typhi, the causative agent of typhoid fever; other Salmonella enterica serotypes, which are major causes of bacterial food poisoning; Shigella species that cause dysentery; and Yersinia pestis, which causes plague. Poliovirus, reoviruses, some retroviruses such as HIV, and prions such as the causal agent of scrapie follow the same entry route. After entry into the M cell, bacteria produce proteins that reorganize the M-cell cytoskeleton in a manner that encourages their transcytosis.


Immunology_Janeway

Immunology_Janeway. The basal cell membrane of an M cell is extensively folded, forming a pocket that encloses lymphocytes and which makes close contacts with local myeloid cells, including dendritic cells (see Fig. 12.7). Macrophages and dendritic cells take up the transported material released from the M cells and process it for presentation to T lymphocytes. Local dendritic cells are in a favorable position to acquire gut antigens, and they are recruited toward, or even into, the follicle-associated epithelium in response to chemokines that are released constitutively by the epithelial cells. The chemokines include CCL20 (MIP-3α) and CCL9 (MIP-1γ), which bind to the receptors CCR6 and CCR1, respectively, on dendritic cells (see Appendix IV for a listing of chemokines and their receptors). The antigen-loaded dendritic cells then migrate from the dome region to the T-cell areas of the Peyer’s patch, where they meet naive, antigen-specific T cells. Together, the dendritic cells and primed T cells then


Immunology_Janeway

Immunology_Janeway. dendritic cells then migrate from the dome region to the T-cell areas of the Peyer’s patch, where they meet naive, antigen-specific T cells. Together, the dendritic cells and primed T cells then activate B cells and initiate class switching to IgA. All these processes— the uptake of antigen by M cells, the migration of dendritic cells into the epithelial layer, the production of chemokines, and the subsequent migration of dendritic cells into T-cell areas—are markedly increased in the presence of pathogenic organisms and their products due to the ligation of pattern recognition receptors on epithelial cells and immune cells (see Section 3-5). Similar processes also underlie the induction of immune responses in isolated lymphoid follicles of the gut and in the MALT of other mucosal surfaces.


Immunology_Janeway

Immunology_Janeway. 12-4 The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease. In addition to the organized lymphoid organs, mucosal surfaces such as the gut and lung contain enormous numbers of lymphocytes and other leukocytes scattered throughout the tissue. Most of the scattered lymphocytes have the appearance of cells that have been activated by antigen, and they comprise the effector T cells and plasma cells of the mucosal immune system. In the intestine, effector cells are found in two main compartments: the epithelium and the lamina propria (see Fig. 12.5).


Immunology_Janeway

Immunology_Janeway. These tissues are quite distinct in immunological terms, despite being separated by only a thin layer of basement membrane. The lymphoid component of the epithelium consists mainly of lymphocytes, which in the small intestine are virtually all CD8 T cells. The lamina propria contains many types of immune cells, including IgA-producing plasma cells, conventional CD4 and CD8 T cells with effector and memory phenotypes, innate lymphoid cells, dendritic cells, macrophages, and mast cells. T cells in the lamina propria of the small intestine express the integrin α4:β7 and the chemokine receptor CCR9 (Fig. 12.8), which attracts them into the tissue from the bloodstream. Intraepithelial lymphocytes (IELs) are mostly CD8 T cells and express either the conventional


Immunology_Janeway

Immunology_Janeway. Fig. 12.8 Priming of naive T cells and the redistribution of effector T cells in the intestinal immune system. Naive T cells carry the chemokine receptor CCR7 and L‑selectin, which direct their entry into Peyer’s patches via high endothelial venules (HEVs). In the T‑cell area they encounter antigen that has been transported into the lymphoid tissue by M cells and is presented by local dendritic cells. During activation, and under the selective control of gut‑derived dendritic cells, the T cells lose L‑selectin and acquire the chemokine receptor CCR9 and the integrin α4:β7. After activation, but before full differentiation, the primed T cells exit from the Peyer’s patch via the draining lymphatics, passing through the mesenteric lymph node to enter the thoracic duct. The thoracic duct empties into the bloodstream, delivering the activated T cells back to the wall of the small intestine. Here T cells bearing CCR9 and α4:β7 are attracted specifically to leave the bloodstream and enter


Immunology_Janeway

Immunology_Janeway. into the bloodstream, delivering the activated T cells back to the wall of the small intestine. Here T cells bearing CCR9 and α4:β7 are attracted specifically to leave the bloodstream and enter the lamina propria of the villus.


Immunology_Janeway

Immunology_Janeway. bloodvessellaminapropriaCCR10CCR9MAdCAM-1˜4:°7Gut-homing effector T cells bind MAdCAM-1 on endothelium largeintestinesmallintestineendotheliumepitheliumCCL25E-cadherin˜E:°7CCL28Gut epithelial cells express chemokines specifc for gut-homing T cells Fig. 12.9 Molecular control of intestine-specific homing of lymphocytes. α:β form of CD8 or the CD8α:α homodimer, which may act to dampen T-cell activation. These IELs express CCR9 and the integrin αE:β7 (CD103), which binds to E-cadherin on epithelial cells (Fig. 12.9). By contrast, in the lamina propria it is CD4 T cells that predominate.


Immunology_Janeway

Immunology_Janeway. The healthy intestinal mucosa therefore displays many characteristics of a chronic inflammatory response—namely, the presence of numerous effector lymphocytes and other leukocytes in the tissues. The presence of such large numbers of effector cells would be unusual for a healthy nonlymphoid tissue, but in the gut does not necessarily signify infection. Rather, it is the local response to the myriad innocuous antigens normally present at mucosal surfaces, and is essential for maintaining the beneficial symbiosis between host and microbiota. It involves a balanced generation of effector and regulatory T cells, but, when required, can be refocused to produce a full adaptive immune response to invading pathogens. 12-5 The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors.


Immunology_Janeway

Immunology_Janeway. The entry of effector lymphocytes into the mucosa results from changes in their homing characteristics as they become activated. Naive T cells and B cells circulating in the bloodstream are not predetermined as to which compartment of the immune system they will end up in, and they enter Peyer’s patches and mesenteric lymph nodes through high endothelial venules (HEVs) (see Fig. 9.4). As in the systemic immune system, this process is controlled largely by the chemokines CCL21 and CCL19, which are released from the lymphoid tissues and bind the receptor CCR7 on naive lymphocytes. In the Peyer’s patches, this is assisted by binding of the mucosal vascular addressin MAdCAM-1 on HEVs to the L-selectin expressed on naive T cells. CXCR5 responding to CXCL13 produced in B-cell follicles is also important for recruitment of naive B cells to Peyer’s patches and isolated lymphoid follicles of the intestine. As in other secondary lymphoid tissues, if the naive lymphocytes do not see their


Immunology_Janeway

Immunology_Janeway. also important for recruitment of naive B cells to Peyer’s patches and isolated lymphoid follicles of the intestine. As in other secondary lymphoid tissues, if the naive lymphocytes do not see their antigen, they exit via the lymphatics and return to the bloodstream. If they encounter antigen in the GALT, the lymphocytes become activated and lose expression of CCR7 and L-selectin. This means that they have lost their ability to home to secondary lymphoid organs, because they cannot enter them via the HEVs (see Section 9-5).


Immunology_Janeway

Immunology_Janeway. Left panel: T and B lymphocytes primed by antigen in the Peyer’s patches or mesenteric lymph nodes arrive as effector lymphocytes in the bloodstream supplying the intestinal wall (see Fig. 12.8). The lymphocytes express the integrin α4:β7, which binds specifically to MAdCAM‑1 expressed selectively on the endothelium of blood vessels in mucosal tissues. This provides the adhesion signal needed for the emigration of cells into the lamina propria. Right panel: if primed in the small intestine, the effector lymphocytes also express the chemokine receptor CCR9, which allows them to respond to CCL25 (yellow circles) produced by epithelial cells of the small intestine; this enhances selective recruitment. Effector lymphocytes that have been primed in the large intestine do not express CCR9 but instead express CCR10. CCR10 may respond to CCL28 (blue circles) produced by colon epithelial cells to fulfill a similar function. Lymphocytes destined to enter the epithelial layer stop expressing the


Immunology_Janeway

Immunology_Janeway. express CCR10. CCR10 may respond to CCL28 (blue circles) produced by colon epithelial cells to fulfill a similar function. Lymphocytes destined to enter the epithelial layer stop expressing the α4:β7 integrin and instead express the αE:β7 integrin. The receptor for this is E‑cadherin on the epithelial cells. These interactions may help keep lymphocytes in the epithelium once they have entered it.


Immunology_Janeway

Immunology_Janeway. Lymphocytes that have been activated in the mucosal lymphoid organs then travel to the mucosa, where they accumulate as effector cells. Although some T and B lymphocytes initially activated in Peyer’s patches may migrate directly into adjacent parts of the lamina propria, most leave via the lymphatics, pass through mesenteric lymph nodes, and eventually end up in the thoracic duct. From there they circulate in the bloodstream (see Fig. 12.8) and selectively reenter the intestinal lamina propria via small blood vessels. Antigen-specific naive B cells in the follicular areas of Peyer’s patches undergo isotype switching from IgM to IgA production there, but they only differentiate fully into IgAproducing plasma cells once they have returned to the lamina propria. As a result, plasma cells are rarely found in Peyer’s patches, and this is also true of effector T cells, which also only differentiate fully after arrival in the mucosa.


Immunology_Janeway

Immunology_Janeway. Gut-specific homing by antigen-stimulated T and B cells is determined in large part by the expression of the adhesion molecule α4:β7 integrin on the lymphocytes. This binds to the mucosal vascular addressin MAdCAM-1, found on the endothelial cells that line the blood vessels within the gut wall (see Fig. 12.9). Lymphocytes originally primed in the gut are also lured back as a result of tissue-specific expression of chemokines by the gut epithelium. In the case of the small intestine, CCL25 (TECK) produced constitutively by epithelial cells is a ligand for the receptor CCR9 expressed on gut-homing T cells and B cells. Within the intestine there seems to be regional specialization of chemokine expression, as CCL25 is not expressed outside the small intestine and CCR9 is not required for migration of lymphocytes to the colon. However, the colon, lactating mammary gland, and salivary glands express CCL28 (MEC, mucosal epithelial chemokine), which is a ligand for the receptor CCR10 on


Immunology_Janeway

Immunology_Janeway. migration of lymphocytes to the colon. However, the colon, lactating mammary gland, and salivary glands express CCL28 (MEC, mucosal epithelial chemokine), which is a ligand for the receptor CCR10 on gut-primed lymphocytes and attracts IgA-producing B lymphoblasts to these tissues. The addressins and chemokine receptors involved in migration of activated lymphocytes to other mucosal surfaces are unknown.


Immunology_Janeway

Immunology_Janeway. Under most normal circumstances, only lymphocytes that first encounter antigen in a gut-associated secondary lymphoid organ are induced to express gut-specific homing receptors and integrins. As we shall see in the next sections, these molecules are induced or ‘imprinted’ on T lymphocytes by intestinal dendritic cells during antigen presentation. In contrast, dendritic cells from nonmucosal lymphoid tissues induce lymphocytes to express other adhesion molecules and chemokine receptors—for example, α4:β1 integrin (VLA-4), which binds VCAM-1; cutaneous lymphocyte antigen (CLA), which binds E-selectin; and the chemokine receptor CCR4—which direct them to tissues such as the skin (see Section 11-3). The tissue-specific consequences of lymphocyte priming in the GALT explain why effective vaccination against intestinal infections requires immunization by a mucosal route, because other routes, such as subcutaneous or intramuscular immunization, do not involve dendritic cells with the correct


Immunology_Janeway

Immunology_Janeway. against intestinal infections requires immunization by a mucosal route, because other routes, such as subcutaneous or intramuscular immunization, do not involve dendritic cells with the correct imprinting properties.


Immunology_Janeway

Immunology_Janeway. 12-6 Priming of lymphocytes in one mucosal tissue may induce protective immunity at other mucosal surfaces.


Immunology_Janeway

Immunology_Janeway. Not all parts of the mucosal immune system exploit the same tissue-specific chemokines, allowing localized compartmentalization of lymphocyte recirculation within the system. Thus, effector T and B cells primed in lymphoid organs draining the small intestine (mesenteric lymph nodes and Peyer’s patches) are most likely to return to the small intestine; similarly, those primed in the respiratory tract migrate most efficiently back to the respiratory mucosa. This homing is obviously useful in returning antigen-specific effector cells to the mucosal organ in which they will be most effective in fighting an infection or in controlling immune responses against foreign proteins and commensals. Nevertheless, some lymphocytes that have been primed in the GALT, for example, can also recirculate as effector cells to other mucosal tissues such as the respiratory tract, urogenital tract, and lactating breast. This overlap between mucosal recirculation routes gave rise to the idea of a common


Immunology_Janeway

Immunology_Janeway. as effector cells to other mucosal tissues such as the respiratory tract, urogenital tract, and lactating breast. This overlap between mucosal recirculation routes gave rise to the idea of a common mucosal immune system, which is distinct from other parts of the immune system. Although this is now understood to be an oversimplification, it does have important implications for vaccine development, because it may enable immunization by one mucosal route to be used to protect against infection at another mucosal surface. An important example of this is the induction of IgA antibody production in the lactating breast by natural infection or vaccination of mucosal surfaces such as the intestine. This is because the vasculature of the lactating breast expresses MAdCAM-1 and the phenomenon is a crucial means of generating protective immunity that can be transmitted to infants by passive transfer of the antibodies in milk. A further example has been shown in experimental animals, in which


Immunology_Janeway

Immunology_Janeway. a crucial means of generating protective immunity that can be transmitted to infants by passive transfer of the antibodies in milk. A further example has been shown in experimental animals, in which nasal immunization has a special ability to prime immune responses in the urogenital tract against HIV. The mechanisms behind this are unknown.


Immunology_Janeway

Immunology_Janeway. 12-7 Distinct populations of dendritic cells control mucosal immune responses.


Immunology_Janeway

Immunology_Janeway. As elsewhere, dendritic cells are important for initiating and shaping immune responses in mucosal tissues, and are located both in secondary mucosal lymphoid organs and scattered throughout the mucosal surfaces. Within Peyer’s patches, dendritic cells are found in two main areas. In the subepithelial dome region, dendritic cells can acquire antigen from M cells (Fig. 12.10). Both of the major subtypes of dendritic cells are present in the intestine (see Sections 6-5 and 9-1). In mice, the most abundant subset of dendritic cells in the Peyer’s patch expresses CD11b (αM integrin) and, when activated, tends to produce IL-23. This promotes development of TH17 cells and stimulates ILC3 cells, both of which produce IL-17 and IL-22 (see Sections 3-23 and 11-2). These dendritic cells express CCR6, the receptor for CCL20 produced by follicle-associated epithelial cells. In resting conditions, they reside beneath the epithelium and produce IL-10 in response to antigen uptake, maintaining a


Immunology_Janeway

Immunology_Janeway. CCR6, the receptor for CCL20 produced by follicle-associated epithelial cells. In resting conditions, they reside beneath the epithelium and produce IL-10 in response to antigen uptake, maintaining a noninflammatory environment. However, during infection by a pathogen such as Salmonella, dendritic cells are rapidly recruited into the epithelial layer of the Peyer’s patch in response to the CCL20 that is released in increased quantities by epithelial cells in the presence of the bacteria. Bacterial products also activate the dendritic cells to express co-stimulatory molecules, allowing them to induce pathogen-specific naive T cells to differentiate into effector cells. Also in the T-cell area of Peyer’s patches are the less abundant CD11b-negative subset of dendritic cells, whose development requires the factor BATF3 and which produce the cytokine IL-12 (see Sections 6-5 and 9-9). CD11b-expressing dendritic cells are protective in many intestinal infections.


Immunology_Janeway

Immunology_Janeway. Dendritic cells are also abundant in the wall of the small intestine outside Peyer’s patches, mainly in the lamina propria. These sample antigens from the lumen and surrounding tissue, and they spend a relatively short time in the intestine before migrating in afferent lymph to the draining mesenteric lymph node, where they present antigen to naive T cells. As elsewhere, migration of dendritic cells depends on the chemokine receptor CCR7 (see Fig. 9.17). It is estimated that 5–10% of the mucosal dendritic cell population emigrates to the mesenteric lymph nodes every day in the resting intestine, allowing constant delivery of antigens from the intestinal surface to T cells. In the absence of infection or inflammation, the encounter between migrating dendritic cells and naive T cells in mesenteric lymph nodes results in the generation of antigen-specific FoxP3+ regulatory T cells that express the gut-homing molecules CCR9 and integrin α4:β7 described above (see Section 12-4). These


Immunology_Janeway

Immunology_Janeway. mesenteric lymph nodes results in the generation of antigen-specific FoxP3+ regulatory T cells that express the gut-homing molecules CCR9 and integrin α4:β7 described above (see Section 12-4). These ‘primed’ Treg cells then leave the lymph node, return to the wall of the small intestine, and suppress the production of inflammatory responses to harmless antigens in food.


Immunology_Janeway

Immunology_Janeway. Fig. 12.10 Capture of antigens from the intestinal lumen by mononuclear cells in the lamina propria. Top row, first panel: soluble antigens such as food proteins can be transported directly across or between enterocytes, or taken up by M cells in the surface epithelium outside Peyer’s patches. Second panel: enterocytes can capture and internalize antigen:antibody complexes by means of the neonatal Fc receptor (FcRn) on their surface and transport them across the epithelium by transcytosis. Lamina propria dendritic cells express FcRn and other Fc receptors and capture and internalize the complexes. Third panel: an enterocyte infected with an intracellular pathogen undergoes apoptosis and is phagocytosed by a dendritic cell. Lower rows, left panels: mononuclear cells can extend cellular processes between the cells of the epithelium without disturbing its integrity. These cells, now thought to be macrophages, may internalize antigen and pass it to neighboring dendritic cells for


Immunology_Janeway

Immunology_Janeway. processes between the cells of the epithelium without disturbing its integrity. These cells, now thought to be macrophages, may internalize antigen and pass it to neighboring dendritic cells for presentation to T cells. The micrograph shows mononuclear cells stained for CD11c (green) in the lamina propria of a villus of mouse small intestine. The epithelium appears black but its luminal (outer) surface is shown by the white line. A cell process stretches between two epithelial cells and extends its tip into the lumen of the intestine. Magnification ×200. Center panels: mucus‑secreting goblet cells can transport soluble antigens to lamina propria dendritic cells. The micrograph shows the soluble marker dextran (purple) being transported across goblet cells (white in the bottom right panel) in the epithelium (nuclei stained blue) to underlying dendritic cells (stained for CD11c in green). Scale bar 10 μm. Right panels: dendritic cells (purple) may enter the epithelial layer and capture


Immunology_Janeway

Immunology_Janeway. in the epithelium (nuclei stained blue) to underlying dendritic cells (stained for CD11c in green). Scale bar 10 μm. Right panels: dendritic cells (purple) may enter the epithelial layer and capture bacteria before returning to the lamina propria. Dendritic cells and macrophages remaining in the lamina propria are stained blue or green. Scale bar 10 μm. Bottom left, micrograph from Niess, J.H., et al.: Science 2005, 307:254–258. Bottom center, micrograph from McDole, J.R., et al.: Nature 2012, 483:345–349. Bottom right, micrograph from Farache et al.: Immunity 2013, 38:581–595.


Immunology_Janeway

Immunology_Janeway. Both the generation of Treg cells and their expression of gut-homing molecules require that the dendritic cells produce retinoic acid, which is derived from the metabolism of dietary vitamin A through the action of retinal dehydrogenases. Retinoic acid is also produced by stromal cells in the mesenteric lymph node, further enhancing the effects of the migratory dendritic cells. Retinoic acid-producing dendritic cells are also found in Peyer’s patches, and may also be important for generating regulatory T cells either in the Peyer’s patch itself, or after they migrate to the mesenteric lymph node. The induction of regulatory T cells in intestinal tissues is assisted by transforming growth factor-β (TGF-β), which is produced by dendritic cells. Migratory populations of dendritic cells that continuously take up local antigens in the tissue and transport them to the draining lymph nodes are also found in the large intestine and other mucosal surfaces such as the lung. Although it is


Immunology_Janeway

Immunology_Janeway. that continuously take up local antigens in the tissue and transport them to the draining lymph nodes are also found in the large intestine and other mucosal surfaces such as the lung. Although it is believed dendritic cells from these tissues are also involved in maintaining tolerance to harmless materials such as commensal bacteria, they do not produce retinoic acid, and it is not clear how they influence T-cell differentiation and homing.


Immunology_Janeway

Immunology_Janeway. The dendritic cells in the intestinal lamina propria also include the two major subsets described above. Collectively, the properties of intestinal dendritic cells result in a dominantly tolerogenic environment that prevents unnecessary and damaging reactions to foods and commensal microorganisms. The anti-inflammatory behavior of mucosal dendritic cells in the healthy gut is promoted by factors that are constitutively produced in the mucosal environment. These include thymic stromal lymphopoietin (TSLP), TGF-β produced by dendritic and epithelial cells, prostaglandin PGE2 produced by stromal cells, and IL-10 produced by intestinal macrophages and CD4 T cells. Retinol stored in the liver and delivered into the small intestine via the bile provides an additional source for the local generation of retinoic acid for conditioning dendritic cells in the wall of the small intestine. 12-8 Macrophages and dendritic cells have different roles in mucosal immune responses.


Immunology_Janeway

Immunology_Janeway. 12-8 Macrophages and dendritic cells have different roles in mucosal immune responses. The lamina propria of the healthy intestine contains the largest population of macrophages in the body. Like dendritic cells, they express CD11c and class II MHC, but unlike dendritic cells in this site, they lack CD103 expression, but express FcγR1 (CD64; see Fig. 10.38) and CX3CR1, the receptor for CX3CL1 (fractalkine). Macrophages are also unable to migrate from the intestine to the draining lymph nodes and cannot present antigen to naive T cells. Unlike many other tissue-resident macrophages, such as those in the brain or liver, which develop from embryonic precursors (see Section 3-1), those in the intestine require constant replenishment by blood monocytes.


Immunology_Janeway

Immunology_Janeway. Macrophages are important for maintaining a healthy intestine. They are positioned immediately under the epithelium and are highly phagocytic, and thus ideally suited to ingest and degrade any microbes that penetrate across the epithelial barrier. They can also clear away dying epithelial cells, which are found in large numbers in the intestine, an inevitable consequence of such a rapidly dividing tissue. However, unlike macrophages in other parts of the body, intestinal macrophages do not produce significant quantities of inflammatory cytokines or reactive oxygen or nitrogen species in response to phagocytosis or exposure to stimuli such as bacteria or TLR ligands. This is because they produce large amounts of IL-10 constitutively, allowing them to limit inflammation while acting as powerful scavengers. Macrophage-derived IL-10 also contributes to maintaining antigen-specific tolerance in the mucosa, as it is needed to sustain the survival and secondary expansion of FoxP3+ Treg cells


Immunology_Janeway

Immunology_Janeway. scavengers. Macrophage-derived IL-10 also contributes to maintaining antigen-specific tolerance in the mucosa, as it is needed to sustain the survival and secondary expansion of FoxP3+ Treg cells that have migrated back to the intestine after being primed by tolerogenic dendritic cells in the lymph node. Indeed, they have features of both these populations, and their functions are specifically adapted to the conditions of their local environment. Thus macrophages and dendritic cells play distinct but complementary roles in the steady-state intestine. Migratory dendritic cells carry out the initial priming and shaping of T-cell responses in secondary lymphoid organs, and sessile macrophages scavenge cellular debris and microbes and may tune the activity of already primed T cells in the mucosa itself.


Immunology_Janeway

Immunology_Janeway. 12-9 Antigen-presenting cells in the intestinal mucosa acquire antigen by a variety of routes.


Immunology_Janeway

Immunology_Janeway. The total surface area provided by M cells in the epithelium of Peyer’s patches for antigen to the intestinal immune system is limited, and the lamina propria itself is covered by an intact epithelium. Various additional mechanisms have been proposed to explain how antigen crosses the epithelium to gain access to macrophages and dendritic cells (see Fig. 12.10). Soluble antigens such as food proteins might be transported across epithelial cells or between gaps formed in the epithelium where dying cells are being shed. Alternatively, M cells may reside in the surface epithelium of the mucosa outside Peyer’s patches. Some intestinal bacteria, such as enteropathogenic and enterohemolytic strains of E. coli, have specialized means of attaching to and invading epithelial cells, allowing them to enter the underlying lamina propria directly. Antigen from the lumen can be delivered to lamina propria dendritic cells by uptake of antibody-coated antigens by epithelial cells expressing the


Immunology_Janeway

Immunology_Janeway. to enter the underlying lamina propria directly. Antigen from the lumen can be delivered to lamina propria dendritic cells by uptake of antibody-coated antigens by epithelial cells expressing the neonatal Fc receptor (FcRn). Antigen derived from apoptotic epithelial cells may be processed by cross-presenting dendritic cells (see Section 6-5) for induction of immune responses against enteric viruses, such as rotaviruses, which cause diarrheal disease because of their specialized ability to infect enterocytes (see Fig. 12.10).


Immunology_Janeway

Immunology_Janeway. Macrophages in the lamina propria may also participate in local antigen uptake by sending transepithelial dendrites that extend between epithelial cells and reach the lumen to sample bacteria (see Fig. 12.10). Lamina propria macrophages have also been reported to take up soluble antigen from the lumen, passing it on to dendritic cells for subsequent presentation to T cells. Some experiments also suggest that dendritic cells or macrophages might make their way into the lumen to acquire antigens such as bacteria, before returning with them to the lamina propria. 12-10 Secretory IgA is the class of antibody associated with the mucosal immune system.


Immunology_Janeway

Immunology_Janeway. 12-10 Secretory IgA is the class of antibody associated with the mucosal immune system. The dominant class of antibody in the mucosal immune system is IgA, which is produced locally by plasma cells in the mucosal wall. The nature of IgA differs between the two main compartments in which it is found—the blood and mucosal secretions. IgA in the blood is mainly in the form of a monomer (mIgA) that is produced in the bone marrow by plasma cells derived from B cells activated in lymph nodes. In mucosal tissues, IgA is produced almost exclusively as a polymer, usually as a dimer, in which the two immunoglobulin monomers are linked by a J chain (see Section 5-16).


Immunology_Janeway

Immunology_Janeway. The naive B-cell precursors of the IgA-secreting mucosal plasma cells are activated in Peyer’s patches and mesenteric lymph nodes. Class switching of activated B cells to IgA is controlled by the cytokine TGF-β. In the human gut, this class switching is entirely T-cell dependent and occurs only in organized lymphoid tissues, where follicular helper T cells (TFH) instruct B cells by the same mechanisms as described in Chapter 10. The subsequent expansion and differentiation of IgA-switched B cells are driven by IL-5, IL-6, IL-10, and IL-21. Upward of 75,000 IgA-producing plasma cells are present in the normal human intestine, and 3–4 g of IgA is secreted by the mucosal tissues each day, and is the major immunoglobulin class produced there. This continuous production of large quantities of IgA occurs in the absence of pathogenic invasion and is driven almost entirely by recognition of the commensal microbiota.


Immunology_Janeway

Immunology_Janeway. In humans, monomeric and dimeric IgA are both found as two isotypes, IgA1 and IgA2. The ratio of IgA1 to IgA2 varies markedly depending on the tissue, being about 10:1 in the blood and upper respiratory tract, about 3:2 in the small intestine, and 2:3 in the colon. Some common pathogens of the respiratory mucosa (such as Haemophilus influenzae) and the genital mucosa (such as Neisseria gonorrhoeae) produce proteolytic enzymes that can cleave IgA1, whereas IgA2 is resistant to cleavage. The higher proportion of plasma cells secreting IgA2 in the large intestine might result because the high density of commensal microorganisms at this site drives the production of cytokines that cause selective class switching. In mice, only one IgA isotype is found, and it is most closely similar to IgA2 in humans.


Immunology_Janeway

Immunology_Janeway. After activation and differentiation, the resulting IgA-expressing B lymphoblasts express the mucosal homing integrin α4:β7, as well as the chemokine receptors CCR9 and CCR10, and localize to mucosal tissues by the mechanisms discussed above. Once in the lamina propria, the B cells undergo final differentiation into plasma cells, which synthesize IgA dimers and secrete them into the subepithelial space (Fig. 12.11). To reach its target antigen in the gut lumen, the IgA has to be transported across the epithelium by the polymeric immunoglobulin receptor (pIgR), which we introduced in Section 10-16. pIgR is expressed constitutively on the basolateral surfaces of the immature epithelial cells located at the base of the intestinal crypts and binds covalently to the Fc portion of J-chain-linked polymeric immunoglobulins such as dimeric IgA and pentameric IgM, and it transports the antibody by transcytosis to the luminal surface of the epithelium, where it is released by proteolytic


Immunology_Janeway

Immunology_Janeway. polymeric immunoglobulins such as dimeric IgA and pentameric IgM, and it transports the antibody by transcytosis to the luminal surface of the epithelium, where it is released by proteolytic cleavage of the extracellular domain of the receptor. Part of the cleaved pIgR remains associated with the IgA and is known as secretory component (frequently abbreviated to SC). The resulting antibody is protected from proteolytic cleavage and is referred to as secretory IgA (SIgA).


Immunology_Janeway

Immunology_Janeway. In some animals there is a second route of IgA secretion into the intestine— the hepatobiliary route. Dimeric IgA that has not bound pIgR is taken up into venules in the lamina propria, which drain intestinal blood to the liver via the portal vein. In the liver these small veins (sinusoids) are lined by an endothelium that allows the antibodies access to underlying hepatocytes, which have pIgR on their surface. IgA is taken up into the hepatocytes and transported by transcytosis into an adjacent bile duct. In this way, secretory IgA can be delivered directly into the upper small intestine via the common bile duct. This hepatobiliary route allows dimeric IgA to eliminate antigens that have invaded the lamina propria and have been bound there by IgA. Although highly efficient in rats and other rodents, this route does not seem to be of great significance in humans and other primates, in whom hepatocytes do not express pIgR.


Immunology_Janeway

Immunology_Janeway. IgA secreted into the gut lumen binds to the layer of mucus coating the epithelial surface via carbohydrate determinants in secretory component. There it is involved in preventing invasion by pathogenic organisms and, just as important, it also has a crucial role in maintaining the homeostatic balance


Immunology_Janeway

Immunology_Janeway. Fig. 12.11 Transcytosis of IgA antibody across epithelia is mediated by the polymeric Ig receptor (pIgR), a specialized transport protein. Most IgA antibody is synthesized in plasma cells lying just beneath epithelial basement membranes of the gut, the respiratory epithelia, the tear and salivary glands, and the lactating mammary gland. The IgA dimer linked by a J chain diffuses across the basement membrane and is bound by the pIgR on the basolateral surface of the epithelial cell. The bound complex undergoes transcytosis, by which it is transported in a vesicle across the cell to the apical surface. There the pIgR is cleaved, leaving the extracellular IgA‑binding component bound to the IgA molecule as the so‑called secretory component. Although not shown, carbohydrate on the secretory component binds to mucins in mucus and holds the IgA at the epithelial surface. The residual piece of the pIgR is nonfunctional and is degraded. IgA is transported across epithelia in this way into the


Immunology_Janeway

Immunology_Janeway. binds to mucins in mucus and holds the IgA at the epithelial surface. The residual piece of the pIgR is nonfunctional and is degraded. IgA is transported across epithelia in this way into the lumina of several organs that are in contact with the external environment.


Immunology_Janeway

Immunology_Janeway. Fig. 12.12 Mucosal IgA has several functions in epithelial surfaces. First panel: IgA adsorbs on the layer of mucus covering the epithelium, where it can neutralize pathogens and their toxins, preventing their access to tissues and inhibiting their functions. Second panel: antigen internalized by the epithelial cell can meet and be neutralized by IgA in endosomes. Third panel: toxins or pathogens that have reached the lamina propria encounter pathogen‑specific IgA there, and the resulting complexes are reexported into the lumen across the epithelial cell as the dimeric IgA is secreted. Fourth panel: antigen bound to secretory IgA in the lumen can bind via carbohydrate residues on the Fc portion of IgA to Dectin‑1 on M cells in Peyer’s patches and be transported to underlying dendritic cells. Binding of the IgA‑containing complex to DC‑SIGN on the dendritic cells induces them to produce anti‑inflammatory IL‑10.


Immunology_Janeway

Immunology_Janeway. between the host and the commensal microbiota. It does this in a number of ways (Fig. 12.12). First, it inhibits microbial adherence to the epithelium, its ability to bind bacteria being assisted by the unusually wide and flexible angle between the Fab pieces of the IgA molecule, particularly the IgA1 isotype (see Section 5-12), allowing very efficient bivalent binding to large antigens such as bacteria. Secretory IgA can also neutralize microbial toxins or enzymes.


Immunology_Janeway

Immunology_Janeway. In addition to its activities in the lumen, IgA can neutralize bacterial lipopolysaccharide and viruses it encounters within endosomes inside epithelial cells, as well as across the epithelial barrier in the lamina propria after bacteria and viruses have penetrated there. The resulting IgA:antigen complexes are then reexported into the gut lumen, from where they are excreted from the body (see Fig. 12.12). Complexes containing dimeric IgA formed in the lamina propria can also be excreted via the hepatobiliary route described above. In addition to enabling the elimination of antigens, the formation of IgA:antigen complexes can enhance the uptake of luminal antigen by M cells and local dendritic cells, via binding of carbohydrate residues on IgA to lectin receptors such as Dectin-1 and DC-SIGN. As well as these antigen-specific effects, secretory IgA can restrict the entry of bacteria in a nonspecific manner. This is because the high carbohydrate content of the Fc part of the IgA heavy


Immunology_Janeway

Immunology_Janeway. As well as these antigen-specific effects, secretory IgA can restrict the entry of bacteria in a nonspecific manner. This is because the high carbohydrate content of the Fc part of the IgA heavy chain allows it to act as a decoy for receptors that bacteria use to bind carbohydrates on the epithelial surface. Secretory IgA has little capacity to activate the classical pathway of complement or to act as an opsonin, and so does not induce inflammation. Uptake of IgA:antigen complexes by dendritic cells also induces these cells to produce anti-inflammatory IL-10. Together these properties mean that IgA can limit the penetration of microbes into the mucosa without risking inflammatory damage to these fragile tissues, something that would be potentially harmful in the intestine. For the same reasons, secretory IgA is crucial to the beneficial symbiosis between an individual and gut commensal bacteria (see Section 12-20).


Immunology_Janeway

Immunology_Janeway. 12-11 T-independent processes can contribute to IgA production in some species.


Immunology_Janeway

Immunology_Janeway. In mice, unlike humans, a significant proportion of intestinal IgA is derived from T-cell-independent B-cell activation and class switching. This depends on activation of the innate immune system by the products of commensal microbes and may result from the direct interaction of B cells with conventional dendritic cells and follicular dendritic cells in solitary lymphoid follicles. This antibody production seems to involve lymphocytes of the B-1 subset (see Section 8-9), which arise from precursor B cells in the peritoneal cavity and migrate to the intestinal wall in response to microbial constituents such as lipopolysaccharide. Once in the mucosa, TGF-β-dependent class switching to IgA occurs under the influence of local factors, including IL-6, retinoic acid, and BAFF and APRIL (see Fig. 10.6), which bind to TACI on B cells substituting for signals otherwise supplied by CD4 helper T cells (see Section 10-1). Intestinal epithelial cells can produce BAFF and APRIL, while local


Immunology_Janeway

Immunology_Janeway. Fig. 10.6), which bind to TACI on B cells substituting for signals otherwise supplied by CD4 helper T cells (see Section 10-1). Intestinal epithelial cells can produce BAFF and APRIL, while local eosinophils may contribute by producing APRIL, IL-6, and TGF-β. Other myeloid cells may produce nitric oxide (NO) and TNF-α, both of which assist in the processing and activation of TGF-β.


Immunology_Janeway

Immunology_Janeway. The IgA antibodies produced in these T-cell-independent responses are of limited diversity and of generally low affinity, with little evidence of somatic hypermutation. They are nevertheless an important source of ‘natural’ antibodies directed at commensal bacteria. As yet, there is little evidence for this source of IgA in humans, in whom all secretory IgA responses involve somatic hypermutation and seem to be T-cell dependent. The enzyme activation-induced cytidine deaminase (AID), which is required for class switching (see Chapter 5), cannot be detected in human intestinal lamina propria, indicating that class switching is unlikely to occur there. Nevertheless, its occurrence in lamina propria B cells in mice may offer a glimpse into the evolutionary history of specific antibody responses in the mucosa, and might indicate pathways that could be activated when T-cell-dependent IgA production is compromised in humans, as it is in AIDS. Nonetheless, it is likely that secondary


Immunology_Janeway

Immunology_Janeway. responses in the mucosa, and might indicate pathways that could be activated when T-cell-dependent IgA production is compromised in humans, as it is in AIDS. Nonetheless, it is likely that secondary reactivation of IgA-committed B lymphoblasts occurs in the lamina propria for full differentiation of plasma cells, which likely involves production by myeloid and epithelial cells of APRIL, BAFF, and other mediators 12-12 IgA deficiency is relatively common in humans but may be compensated for by secretory IgM.


Immunology_Janeway

Immunology_Janeway. Selective deficiency of IgA production is the commonest primary immune deficiency in humans, occurring in about 1 in 500 to 700 individuals in populations of Caucasian origin, although it is somewhat rarer in other ethnic groups. The most frequent genetic mutation that has been identified in this condition is in the TACI receptor for BAFF. A slightly higher incidence of respiratory infections, atopy (a tendency for allergic reactions to harmless environmental antigens), and autoimmune disease has been reported in older people with IgA deficiency. However, most individuals with IgA deficiency are not overly susceptible to infections unless there is also a deficiency in IgG2 production. The dispensability of IgA probably reflects the ability of IgM to replace IgA as the predominant antibody in secretions, and increased numbers of IgM-producing plasma cells are indeed found in the intestinal mucosa of IgA-deficient people. Because IgM is a J-chain-linked polymer, IgM produced in the gut


Immunology_Janeway

Immunology_Janeway. in secretions, and increased numbers of IgM-producing plasma cells are indeed found in the intestinal mucosa of IgA-deficient people. Because IgM is a J-chain-linked polymer, IgM produced in the gut mucosa is bound efficiently by the pIgR and is transported across epithelial cells into the gut lumen as secretory IgM. The importance of this backup mechanism has been shown in knockout mice. Animals lacking IgA alone have a normal phenotype, but those lacking the pIgR are susceptible to mucosal infections. They also show increased penetration of commensal bacteria into tissues and a consequent systemic immune response to these bacteria. Genetic absence of the pIgR has never been reported in humans, suggesting that such a defect is lethal.


Immunology_Janeway

Immunology_Janeway. 12-13 The intestinal lamina propria contains antigen-experienced T cells and populations of unusual innate lymphoid cells. Most of the T cells in the healthy lamina propria have been activated by dendritic cells and express markers of effector or memory T cells, such as CD45RO in humans, and express gut-homing markers such as CCR9 and α4:β7 integrin, as well as receptors for pro-inflammatory chemokines such as CCL5 (RANTES). The T-cell population of the lamina propria has a ratio of CD4 to CD8 T cells of 3:1 or more, similar to that in systemic lymphoid tissues.


Immunology_Janeway

Immunology_Janeway. Lamina propria CD4 T cells secrete large amounts of cytokines such as interferon (IFN)-γ, IL-17, and IL-22, even in the absence of overt inflammation. This likely reflects the constant state of immune recognition of the microbiota and other environmental antigens that takes place in the intestine, and their importance is underlined by the frequent opportunistic infections of the intestine that occur in individuals lacking CD4 T cells, such as those with HIV infection (see Section 13-24). Effector TH17 cells are prominent in the intestinal mucosa, and their products are important components of local immune defense. IL-17 is needed for full expression of the poly-immunoglobulin receptor involved in secretion of IgA into the lumen, while IL-22 stimulates intestinal epithelial cells to produce antimicrobial peptides that help maintain epithelial barrier integrity. Effector CD8 T cells are also present in the normal lamina propria and are capable of both cytokine production and cytotoxic


Immunology_Janeway

Immunology_Janeway. antimicrobial peptides that help maintain epithelial barrier integrity. Effector CD8 T cells are also present in the normal lamina propria and are capable of both cytokine production and cytotoxic activity when a protective immune response to a pathogen is required.


Immunology_Janeway

Immunology_Janeway. In any other situation, the presence of such large numbers of differentiated effector T cells would suggest the presence of a pathogen and likely would lead to inflammation. The fact that it does not in the healthy lamina propria is because the generation of TH1, TH17, and cytotoxic T cells is balanced by the presence of substantial numbers of IL-10-producing regulatory T cells. In the small intestine, these are mostly FoxP3-negative, whereas in the colon, FoxP3positive T cells dominate. Many of the inducible T cells recognize antigens derived from organisms within the microbiota.


Immunology_Janeway

Immunology_Janeway. The healthy lamina propria also contains many innate lymphoid cells (ILCs) (see Sections 1-19 and 9-20). The ILC3 subset is prominent in both human and mouse intestinal mucosa. Mature ILC3s produce IL-17 and IL-22, and some express the NK-cell receptors NKp44 and NKp46. Their development is controlled by the aryl hydrocarbon receptor and the transcription factor RORγT (see Section 9-21). ILC3s are present in secondary lymphoid organs in the intestine and are important for their lymphoid tissue development there. In response to IL-23 secreted by local dendritic cells, ILC3s produce IL-22, which stimulates the epithelium to generate antimicrobial peptides that promote local defense against bacterial and fungal pathogens in the intestine. During the course of inflammatory diseases, ILC3s can acquire the ability to produce IFN-γ in response to IL-12, and combined with their production of IL-17, this endows them with significant pathological properties. IL-5 and IL-13 produced by ILC2s


Immunology_Janeway

Immunology_Janeway. can acquire the ability to produce IFN-γ in response to IL-12, and combined with their production of IL-17, this endows them with significant pathological properties. IL-5 and IL-13 produced by ILC2s form an important layer of T-cell-independent responses to helminth parasites in the intestine, and an equivalent population is involved in allergic reactions in the respiratory tract.


Immunology_Janeway

Immunology_Janeway. CD1-restricted iNKT cells (see Section 6-18) and mucosal invariant T (MAIT) cells (see Section 6-19) are also present in the lamina propria, and account for 2–3% of lamina propria T cells in human small intestine. MAIT cells express an invariant TCRα chain paired with a limited range of TCRβ chain and recognize metabolites of vitamin B derived mainly from the riboflavin metabolism pathway in microbes presented by MR1. 12-14 The intestinal epithelium is a unique compartment of the immune system.


Immunology_Janeway

Immunology_Janeway. 12-14 The intestinal epithelium is a unique compartment of the immune system. We have already introduced the fact that there are abundant intraepithelial lymphocytes (IELs) present in intestine. In the healthy small intestine, there are 10–15 lymphocytes for every 100 epithelial cells, making the IELs one of the single largest populations of lymphocytes in the body (Fig. 12.13). More than 90% of the IELs in the small intestine are T cells, and around 80% of these carry CD8, in complete contrast to the lymphocytes in the lamina propria. IELs are also present in the large intestine, although there are fewer of them relative to the number of epithelial cells and the proportion of CD4 T cells is greater than in the small intestine.


Immunology_Janeway

Immunology_Janeway. Like the lymphocytes in the lamina propria, most IELs have an activated appearance even in the absence of infection by a pathogen, and they contain intracellular granules containing perforin and granzymes, like those in conventional effector CD8 cytotoxic T cells. However, the T-cell receptors of most CD8 IELs show evidence of oligoclonality, with restricted use of V(D)J gene segments, an indication that they may expand locally in response to a relatively small number of antigens. The IELs of the small intestine express the chemokine receptor CCR9, and the αE:β7 integrin (CD103), which interacts with E-cadherin expressed on epithelial cells and assists their retention in the epithelium (see Fig.12.9).


Immunology_Janeway

Immunology_Janeway. Fig.12.13 Intraepithelial lymphocytes. The epithelium of the are CD8 T cells. Magnification ×400. The electron micrograph on small intestine contains a large population of lymphocytes known the right shows that the IELs lie between epithelial cells (EC) on the as intraepithelial lymphocytes (IELs; left panel). The micrograph in basement membrane (BM) separating the lamina propria (LP) from the center is of a section through human small intestine in which the epithelium. One IEL can be seen having crossed the basement CD8 T cells have been stained brown with a peroxidase‑labeled membrane into the epithelium, leaving a trail of cytoplasm in its monoclonal antibody. Most of the lymphocytes in the epithelium wake. Magnification ×8000.


Immunology_Janeway

Immunology_Janeway. There are two main subsets of CD8 intraepithelial T cells—type a (‘inducible’) and type b (‘natural’)—identified based on which form of CD8 is expressed. The relative proportions of the subsets vary with age, strain (in mice), and number of bacteria in the intestine. Type a (inducible) IELs express α:β T-cell receptors and the CD8α:β heterodimer. They are derived from naive CD8 T cells that were activated by antigen in the Peyer’s patches or mesenteric lymph nodes, and they function as conventional class I MHC-restricted cytotoxic T cells, killing virus-infected cells, for example (Fig. 12.14, top panels). They also secrete effector cytokines such as IFN-γ.


Immunology_Janeway

Immunology_Janeway. Type a IELs (top panels) are conventional CD8 cytotoxic T cells that recognize peptides derived from viruses or other intracellular pathogens bound to classical MHC class I molecules on infected epithelial cells. Type a IELs express an α:β T‑cell receptor and the CD8α:β heterodimer co‑receptor. Type b IELs carrying the CD8α:α homodimer (bottom panels) recognize MIC‑A and MIC‑B using the receptor NKG2D and are activated by IL‑15. Human epithelial cells that have been stressed by infection or altered cell growth or by a toxic peptide from the protein α‑gliadin (a component of gluten) upregulate expression of the nonclassical MHC class I molecules MIC‑A and MIC‑B and produce IL‑15. Both types of IELs can kill by the release of perforin and granzyme. Apoptosis of epithelial cells can also be induced by the binding of Fas ligand on the T cell to Fas on the epithelial cell.


Immunology_Janeway

Immunology_Janeway. Type b (natural) CD8 IELs can express either an α:β or a γ:δ T-cell receptor, but are distinguished by their expression of the CD8α:α homodimer. The γ:δ T cells in the intestine are enriched for particular Vγ and Vδ genes and are distinct from those found in other tissues (see Fig. 8.23). Some of the α:β receptors expressed by IELs bind nonconventional ligands, including those presented by MHC class Ib molecules (see Section 6-17). Type b IELs also express molecules typical of natural killer cells, such as the activating C-type lectin NKG2D, which binds to the two MHC-like molecules MIC-A and MIC-B. These are induced on intestinal epithelial cells in response to cellular injury, stress, or ligation of TLRs (see Section 6-16). The injured cells can then be recognized and killed by the IELs, a process that is enhanced by the production of IL-15 by the damaged epithelial cells. Like innate immune cells, type b IELs constitutively express genes associated with inflammation, such as the


Immunology_Janeway

Immunology_Janeway. a process that is enhanced by the production of IL-15 by the damaged epithelial cells. Like innate immune cells, type b IELs constitutively express genes associated with inflammation, such as the production of high levels of cytotoxic molecules, NO, and pro-inflammatory cytokines and chemokines. Their role in the gut may be the rapid recognition and elimination of epithelial cells that express an abnormal phenotype as a result of stress or infection (see Fig. 12.14, bottom panels). Type b IELs are also thought to be important in aiding the repair of the mucosa after inflammatory damage: they stimulate the release of antimicrobial peptides, thus helping to remove the source of the inflammation; and they release cytokines such as keratinocyte growth factor, which promotes epithelial barrier function, and TGF-β, which assists tissue repair, as well as inhibiting local inflammatory reactions.


Immunology_Janeway

Immunology_Janeway. Type b IELs are kept in check by their co-expression of signaling inhibitors, including the immunomodulatory cytokine TGF-β and inhibitory receptors like those found on NK cells. The importance of these control processes is shown by the fact that inappropriate or excess activation of type b IELs may give rise to disease. For example, increased numbers of IELs expressing a γ:δ T-cell receptor are found in celiac disease, which is caused by an abnormal immune response to the wheat protein gluten (see Section 14-17). MIC-Adependent cytotoxic activity of intraepithelial T cells contributes to the intestinal damage in this condition, as certain components of gluten can stimulate the production of IL-15 by epithelial cells and increase expression of MIC-A. These processes lead to killing of epithelial cells by the activated IELs, as described above (see Fig. 12.14, bottom panels).


Immunology_Janeway

Immunology_Janeway. The origin and development of type b IELs has been controversial and is unexplored in humans. Unlike type a IELs, many type b IELs expressing an α:β T-cell receptor seem not to have undergone conventional positive and negative selection (see Chapter 8), and express apparently autoreactive T-cell receptors. The absence of the CD8α:βheterodimer, however, means that these T cells have low affinity for conventional peptide:MHC complexes, because the CD8β chain binds more strongly than the CD8α chain to classical MHC molecules. Type b α:β T-cell receptor-expressing IELs therefore cannot act as self-reactive effector cells. This low affinity for self MHC molecules is also probably the reason that these cells escape negative selection in the thymus. Rather, they appear to develop via a process of so-called agonist selection, in which late double-negative/early double-positive T cells are positively selected in the thymus by unknown ligands and are released immediately to the intestine. Here


Immunology_Janeway

Immunology_Janeway. so-called agonist selection, in which late double-negative/early double-positive T cells are positively selected in the thymus by unknown ligands and are released immediately to the intestine. Here they mature and are induced to express the CD8α:α homodimer under the influence of TGF-β produced by epithelial cells. Nonclassical MHC molecules expressed on the intestinal epithelium are also important for the maturation of these type b IELs. One example of this kind of selection molecule is the thymus leukemia antigen (TL), another nonclassical MHC class I molecule (see Fig. 6.26) found in certain mouse strains which does not present peptides. TL is expressed by intestinal epithelial cells and directly binds CD8α:α with high affinity.


Immunology_Janeway

Immunology_Janeway. Type b IELs expressing a γ:δ T-cell receptor also develop via agonist selection in the thymus, as part of the programmed wave of γ:δ T-cell development (see Fig. 8.23). The expression of this receptor is driven by specific ligands in the thymus and endows these cells with the specific ability to migrate to the intestinal epithelium, where they may be further programmed by the same agonist ligand.


Immunology_Janeway

Immunology_Janeway. The local differentiation events involved in the development of type b IELs require the presence of the cytokine IL-15, which is produced in response to the microbiota and ‘trans-presented’ to IELs in a complex with the IL-15 receptor present on epithelial cells. Type b IEL development is dependent on the aryl hydrocarbon receptor (AhR), a transcription factor activated by various environmental ligands that are derived from brassica and other dietary vegetables. Mice that lack the AhR have reduced numbers of ILC3 and type b IELs and show abnormalities in epithelial barrier repair, reinforcing the view that these unusual lymphocytes play important roles in the innate immune response to local materials in the intestine. Summary.


Immunology_Janeway

Immunology_Janeway. The mucosal tissues of the body such as the intestine and respiratory tract are continuously exposed to enormous amounts of different antigens, which can be either pathogenic invaders or harmless materials such as foods and commensal organisms. Potential immune responses to this antigen load are controlled by a distinct compartment of the immune system, the mucosal immune system, which is the largest in the body. Its unique features include distinctive routes and processes for the uptake and presentation of antigens, exploitation of M cells to transport antigens across the epithelium of Peyer’s patches, and retinoic acid-producing dendritic cells that imprint the T and B cells they activate with gut-homing properties. Dendritic cells also favor the generation of FoxP3-positive Treg cells in the normal gut. Tissue-resident intestinal macrophages contribute to these regulatory processes by phagocytosing antigens without causing inflammation, due to their production of IL-10. Lymphocytes


Immunology_Janeway

Immunology_Janeway. the normal gut. Tissue-resident intestinal macrophages contribute to these regulatory processes by phagocytosing antigens without causing inflammation, due to their production of IL-10. Lymphocytes primed in the mucosa-associated lymphoid tissues acquire specific homing receptors, allowing them to redistribute preferentially back to mucosal surfaces as effector cells. The adaptive immune response in mucosal tissues is characterized by the production of secretory dimeric IgA, and by the presence of distinct populations of memory/effector T cells in the epithelium and lamina propria. CD4 T cells in the lamina propria produce pro-inflammatory cytokines such as IL-17 and IFN-γ even in the absence of overt infection, but this is normally balanced by the presence of IL-10-producing Treg cells. IELs exhibit cytolytic activity and other innate functions that help maintain a healthy epithelial barrier.


Immunology_Janeway

Immunology_Janeway. The mucosal response to infection and regulation of mucosal immune responses. The major role of the mucosal immune response is defense against infectious agents, which include all forms of microorganisms from viruses to multicellular parasites. This means that the host must be able to generate a wide spectrum of immune responses tailored to meet the challenge of individual pathogens; unsurprisingly, many microbes have evolved means of adapting to and subverting the host response. To ensure an adequate response to pathogens, the mucosal immune system needs to be able to recognize and respond to any foreign antigen, but it must not produce the same effector response to a harmless antigen (from food or commensals) as it would to a pathogen. A major role of the mucosal immune system is to balance these competing demands, and how it does this will be the focus of this part of the chapter.


Immunology_Janeway

Immunology_Janeway. 12-15 Enteric pathogens cause a local inflammatory response and the development of protective immunity. Despite the array of innate immune mechanisms in the gut, and stiff competition from the indigenous microbiota, the gut is a frequent site of infection by a wide variety of pathogenic organisms. These include many viruses; enteric bacteria such as Vibrio, Salmonella, and Shigella species; protozoans such as Entamoeba histolytica; and multicellular helminth parasites such as tapeworms and pinworms. These pathogens cause disease in many ways, and as elsewhere in the body, the key to generating protective immunity is the activation of appropriate aspects of the innate immune system.


Immunology_Janeway

Immunology_Janeway. The effector mechanisms of the innate immune system can themselves eliminate most intestinal infections rapidly and without significant spread of the infection beyond the intestine. The essential features of these responses in epithelial surfaces are discussed in Section 2-2 and here we highlight only aspects that are unique or unusual to the intestine. Of these, the most important involve the epithelial cells themselves (Fig. 12.15). The tight junctions between


Immunology_Janeway

Immunology_Janeway. NF˜BTLRNODsCCL2CCL1IL-6CXCL1CXCL8IL-1IL-1IL-18I˜BTLR-5CCL20defensinstightjunctionslysosomephagosomephagophorecaspaseNOD-2TLRs, NOD1, and NOD2 activate NF˜B, inducing the epithelial cell to express in˜ammatory cytokines, chemokines, and other mediators. These recruit and activate neutrophils, macrophages, and dendritic cells Bacteria are recognized by TLRs on cell surface or in intracellular vesicles Bacteria or their products directly entering the cytosol are recognized by NOD1 and NOD2 Activation of in˜ammasome induces production of IL-1, IL-18 which activate myeloid cells and increase barrier integrity Bacteria in cytoplasm or escaping from phagosome are taken into forming autophagosome and destroyed after fusion with lysosome Intracellular infection triggers formation of in˜ammasome Destruction of bacteria in autophagosome