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Intestinal and Pulmonary Mucosal T Cells: Local Heroes Fight to Maintain the Status Quo Leo Lefranc¸ois and Lynn Puddington Center for Integrative Immunology and Vaccine Research, Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030-1319; email: [email protected], [email protected]

Annu. Rev. Immunol. 2006. 24:681–704 First published online as a Review in Advance on January 16, 2006 The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev.immunol.24.021605.090650 c 2006 by Copyright  Annual Reviews. All rights reserved 0732-0582/06/0423-0681$20.00

Key Words mucosal, T lymphocytes, lung, intestine

Abstract Mucosal immunity in the lung and intestine is controlled by complex multifaceted systems. While mucosal T cells are essential for protection against invading pathogens owing to their proximity to the outside world, powerful systems must also be in place to harness ongoing inflammatory processes. In each site, distinct anatomical structures play key roles in mounting and executing both protective and deleterious mucosal T cell responses. Although analogies can be drawn regarding the immune systems of these two organs, there are substantial dissimilarities necessitated by unique physiologic constraints. Here, we discuss how T cell activation and effector function are generated in the mucosae.

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INTRODUCTION

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In terms of total surface area, the major mucosal organs of the body are the lung and the intestine. In essence, a single layer of epithelial cells within each of these tissues separates the inner corpus from the outside world. Although both organs share barrier function as direct portals into the body and are of common endodermal origin, their respiratory or digestive functions engender distinct anatomical and immunological compartments. The anatomical constraints in turn regulate the nature of lymphocyte responses within each organ with regard to lymphocyte subset development, migration, and effector function. The original concept of “the common mucosal immune system” suggests an overall integration of immune responses in anatomically distinct mucosal tissues, particularly with respect to IgA responses, the hallmark of mucosal immunity (1, 2). Although recent data point out major differences in T cell functional capacity within these organ systems, many commonalities also provide potential links between mucosal sites.

ANATOMICAL COMPARTMENTS OF THE MUCOSAL IMMUNE SYSTEM Before discussing the specifics of mucosal T cell responses, it is necessary to define the relevant locations of T cells within the mucosal tissues and the associated “plumbing,” which regulate movement of antigens, antigenpresenting cells (APCs), lymphocytes, and soluble mediators involved in control of the adaptive immune response. There are multiple lymphocyte locales associated with the lung and the intestine, some of which promote highly specialized functions while others may provide common functions in each mucosal site.

Immune Inductive Sites of Mucosae Organized secondary lymphoid tissues are associated with each organ system and are 682

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thought to be the primary sites of T cell response initiation. For antigens derived from the gut lumen, T cell encounter with antigen occurs in the gut-draining mesenteric lymph nodes (MLN) and the Peyer’s patches (PP) (Figure 1). Thus, afferent lymph from the intestine carrying antigen or antigen-bearing APCs, such as dendritic cells (DCs), transits to the MLN. In contrast, there is no afferent lymphatic drainage to the PP so antigens are acquired directly from the intestinal lumen, in part through specialized epithelial cells, termed M cells (M for microvilli or microfold, due to their distinct surface structure), that overlie approximately 10% of the PP (3–5). In the intestine a population of villus M cells has been identified that may also participate in antigen uptake and pathogen entry (6). Similarly, a population of M cells has recently been identified in the lung (7). Efferent lymphatic drainage from the PP can also potentially carry antigen and cells to the MLN (8, 9). Note that immune responses to antigens or infectious agents introduced systemically may be initiated in these sites because blood may carry antigens to mucosal inductive sites (10). Numerous small isolated lymphoid follicles scattered along the wall of the intestine may also be involved in induction of immune responses (11). In the lung, the mediastinal lymph nodes (MedLN), which drain the lower respiratory tract, are major sites of T cell priming (12–16). (The MedLN are also variously termed the tracheobronchial, parathymic, or hilar LN.) Other LN (e.g., cervical) serve the upper respiratory tract (17). Neolymphoid tissue can also be induced by infection and inflammation (18). An example in the lung is the bronchus-associated lymphoid tissue induced by respiratory virus infection (iBALT) (19, 20). Such structures are likely sites of immune response initiation or maintenance. In fact, in mice lacking lymph nodes and spleen, a CD8 T cell response is still initiated but with delayed kinetics following influenza virus infection. The response is protective and appears to be initiated in iBALT (21). Thus, under certain

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Infectious agents Allergens Foods

Mediastinal LN, BALT from lung; PP, mesenteric LN from gut Naive T cell

+

Imprinting of + migratory and functional preferences

Resting DC

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Afferent lymphatics “2nd hit” upon entry tissue-specific functions induced?

DC migration constitutive, enhanced with inflammation Effector and memory T cells

Tblast (effector function?)

Via thoracic duct

(destruct) Tanergic

Treg

Treg

Effector cell

Tmem

Efferent lymphatics

Migration of effector, naive, and memory T cells into bloodstream to lymphoid and nonlymphoid tissues Figure 1 Schematic diagram of mucosal T cell activation and migration. Infectious agents, foodstuffs, or allergens are ingested or inhaled, with subsequent antigen acquisition by APCs resident in mucosal parenchymal tissues. Resting APCs bearing self or innocuous antigens or APCs activated by infection/inflammation migrate via afferent lymphatics to draining LN and induce either tolerance or immunity. Effector cells exit the LN via efferent lymphatics and traffic to nonlymphoid tissues. Entry into mucosal effector sites may result in further activational events that tune tissue-specific effector functions.

circumstances of infection or perhaps chronic inflammation, induced secondary lymphoid tissue can participate in immune response initiation and control.

Effector Sites of Mucosae Once activated in secondary lymphoid tissues, T cells are able to leave the inductive sites

Activated DC

Tblast

Naive

Blood

Naive T cell

and migrate to all nonlymphoid tissues (22). Those lymphocytes capable of entering nonlymphoid tissues during a primary immune response are likely to be effector cells at the time of entry, or immediately thereafter, e.g., upon re-encounter with antigen within the effector site. The environment of antigen presentation is likely unique to the effector site,

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representing the compilation of antigen exposures in that site. For example, the immunological milieu in the gut is influenced by antigens derived from food or commensal bacteria or in the lung from environmental aeroantigens or respiratory infection. Therefore the capacity of cells of the innate immune system to present antigen within each nonlymphoid tissue is likely to be distinct [because dendritic cell populations are distinct in lymph nodes draining different tissues (23, 24)], and this is an area of intense investigation. The lamina propria of the intestine (gut LP) is a loosely organized connective tissue beneath the basement membrane supporting the overlying epithelial cells of the small and large intestine. The LP contains a variety of cells of the innate and adaptive immune system including IgA-producing plasma cells, DCs, macrophages, and T and B cells. Furthermore, the vast majority of T cells present in the gut LP express an effector/memory phenotype (25–27). An additional population of T lymphocytes (the intraepithelial lymphocytes, IELs) are resident within the intraepithelial spaces above the basement membrane and below the tight junctions of the epithelial cells (28, 29). Although IELs are composed in part of unique T cell subsets including TCRγδ and TCRαβCD8αα cells (28, 30, 31), those CD4 or CD8β+ IELs with conventional phenotypes are also largely of the effector/memory phenotype (32, 33). For the lung, effector cells are located primarily in the lung parenchyma and the airways. Although the lung parenchyma appears analogous to the gut LP, there is no cell population in the intestine topologically equivalent to that in the lung airways [those cells removable by bronchoalveolar lavage (BAL), located above the epithelial cells in the airway lumen]. The parenchyma or interstitium of the lung, the lamina propria or lung LP, underlies the basement membrane supporting the overlying epithelial cells, and it is composed of loosely organized connective tissue containing T cells, APCs, and many other cell types

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of hematopoietic origin. Moreover, similar to the gut LP, many of the T cells in the lung LP express effector/memory phenotypes. However, in contrast to the gut, the lung LP in normal mice contains a significant population of naive T cells. T cell entry into the lung airways, as with entry into the intestinal epithelium, is tightly regulated. These T cells, although closely associated with the epithelium, are essentially outside of the body. Nevertheless, airway CD4 and CD8 T cells can mediate protection against respiratory virus infection (34, 35) as well as participate in deleterious inflammatory reactions, such as allergic asthma (36, 37).

INITIATION OF MUCOSAL T CELL RESPONSES Antigen Acquisition The first step necessary for mucosal T cell activation is the acquisition of antigen by APCs. The mechanism of antigen capture in the mucosal tissues is dependent in part on the nature of the immunogen. For example, soluble protein antigens (e.g., some allergens) may be passively absorbed across the epithelial surfaces of the mucosal tissues (38). In contrast, particular pathogens, for example, Salmonella sp. and reovirus, preferentially bind and enter through intestinal PP (39, 40). In some cases, specific receptors have been identified on epithelial cells (e.g., reovirus binding to M cells) that pathogens have subjugated for adherence and entry into the body. Listeria monocytogenes (LM) utilizes epithelial cell Ecadherin as a receptor for internalin, which promotes entry into the epithelium (41). Similar targeting pathways exist for lung-specific infections or certain aeroallergens. For example, in influenza virus infection, only the respiratory epithelial cells express the protease requisite for cleavage of the hemagglutinin protein necessary for production of infectious virus (42). Many allergens contain protease functions that facilitate their entry into the mucosae by cleavage of the tight junction

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proteins between epithelial cells (43, 44). Thus, the form of the antigen and its biological characteristics determine the mode of access into the host. DCs are believed to be essential for activation of naive T cells in the inductive sites of the mucosae. DCs are located in specific regions of the PP, form a contiguous network within the LP of intestine and lung, but are rare or absent from the epithelial layers (with the exception of the trachea) under normal conditions (45, 46). At steady state there is a slow rate of constant traffic of immature DCs from the mucosal tissues via the lymph to the draining LN (i.e., MLN, MedLN) (8, 16, 47–49). Inflammation in the mucosa results in a dramatic increase in numbers of activated DCs and other APCs in nonlymphoid tissues and migration to the draining LN (14, 45, 50). The increase in DCs in response to inflammatory signals is likely the result of recruitment of circulating immature APC precursors from the blood that then undergo development into particular APC subsets as directed by the “inflammatory” microenvironment (51–55). APCs may acquire antigen directly through pinocytosis, as for soluble proteins (by DCs), or via phagocytosis of particulate material (by DCs or macrophages). Particulate antigens are thought to be more immunogenic and include intact bacteria or viruses, as well as material derived from dead and dying cells, or immune complexes (56–60). In addition, some microorganisms actively infect DCs or other cells capable of presenting antigen, whereas others are unable to do so (61–66). Antigen-specific memory B cells are potential APCs, capable of acquiring antigen via cell-surface immunoglobulin. However, their paucity in number and specific localization in lymphoid and nonlymphoid tissue may restrict their ability to restimulate T cells to those colocalized with antigenspecific CD4+ cells. In the intestinal mucosa a novel method for antigen sampling has been visualized. DCs in the LP are able to extend dendrites through the basement membrane and between the ep-

ithelial cells into the gut lumen (46, 67). In this way, antigen and bacteria can be obtained and carried into the body. As DCs in MLN contain material derived from effete intestinal epithelial cells (IEC) (9), perhaps their acquisition by DCs is via this process. Under steady-state conditions, this continuous sampling and migration by DCs is likely responsible for induction and maintenance of T cell tolerance to food antigens and normal flora (68). A similar system is thought to be in place in the lung, although this has not been demonstrated directly. Note also that macrophages, although rare in LN, are present at the border between red and white pulp in the spleen, are abundant in the lung airways and LP, and are also present in the gut LP. Macrophages could potentially serve as APCs, perhaps to initiate T cell recall responses (69). “Activated” macrophages may also be competent to prime naive T cells (70), e.g., perhaps in the context of a mucosal inflammatory response. However, in the respiratory tract of naive mice, it is generally accepted that the resident “resting” macrophages suppress T cell activation via their effects on colocalized DCs (45, 71).

T Cell-APC Interaction in Mucosal Lymphoid Tissues: Induction of Tolerance Versus Immunity Although direct evidence for DC involvement in mucosal T cell responses exists in only a limited number of cases, the current paradigm favors the DC as the requisite APC for initiation of all primary T cell responses irrespective of whether the immunological outcome is immunity or tolerance. However, definitive proof of this idea has been limited until recently (72), owing to the lack of systems in which DCs can be selectively depleted. Although the CD11c-DTR model represents a significant advance to studies of the role of APCs in T cell responses, use of this model is more limited in studies of immune responses in mucosal sites. This limitation is due to the fact that CD11c is expressed by macrophages in the respiratory tract and spleen, which are

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depleted by DT treatment of transgenic mice (73, 74), and the potential complication with subsets of mucosal effector T cells that express CD11c (75, 76). Nonetheless, confocal and intravital imaging analysis is beginning to provide views of T cell-DC interactions in situ and in real time (77–79). A large body of evidence from these studies and others points to the DC as the main initiator of mucosal T cell responses (24, 49, 73, 80–83), although in some cases non-DC APCs may participate in T cell activation. T cell encounter with antigen-bearing DCs in the mucosal inductive sites can result in multiple outcomes depending on the nature and form of the antigen (Figure 1). Administration of protein antigens such as ovalbumin (OVA) either orally or as an aerosol induces antigen-specific T cell tolerance (84– 92). This tolerance is systemic, presumably due to the dissemination of antigen into the blood following absorption in either the lung or the intestine. Tolerance is likely mediated by antigen presented by resting APCs and ultimately results in T cell deletion and/or generation of T cells with immunoregulatory function (93–99). In either case, it has been demonstrated in situations of antigeninduced T cell tolerance in vivo that some level of T cell activation and proliferation occurs prior to deletion (100, 101) or the generation of regulatory T cells (102, 103). Thus, the DC-T cell interaction drives T cell activation but critical signals required to mount a productive immune response are absent. In the absence of Toll-like receptor (TLR) ligands and/or inflammatory cytokines, the DC is unable to provide sufficient costimulation to the T cell, which leads to an abortive event ultimately resulting in deletion or perhaps anergy in the case of CD4 T cells (50, 101, 104–110). Early events in induction of CD4 T cell tolerance versus protective immunity in the MLN have recently been visualized by two-photon videomicroscopy (111). After feeding large quantities of OVA with or without adjuvant to induce either immunity or tolerance, respectively, adoptively transferred

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OVA-specific CD4 T cells behave quite differently. In the tolerogenic situation, the CD4 T cells form smaller and shorter-lived clusters in the MLN than CD4 T cells in the immunityinducing environment. This series of events can be recapitulated for self antigens as well. When a neoself antigen is expressed in the intestinal epithelium in transgenic mice, systemic tolerance is induced (112). However, low levels of antigen may be expressed in the thymus, as are many “tissue-specific” proteins (113, 114). Nevertheless, transfer of naive antigen-specific CD8 T cells into such mice results in T cell accumulation preferentially in the MLN and PP, which indicates that intestinal epithelial cell-derived proteins can gain access to the intestinal inductive sites. Because the model neoself antigen was an engineered OVA protein whose expression was strictly cytoplasmic, this result suggests that DCs in the PP or gut LP are able to acquire epithelial cellderived antigen and present it either directly within the PP or following their migration via the lymphatics to the MLN. Thus, these results are in agreement with the findings cited above showing continuous trafficking of DCs from the intestinal mucosa to the MLN, and they provide a mechanism for induction and maintenance of self tolerance to intestinal epithelial cell-specific self proteins, and potentially other innocuous antigens, such as those derived from food acquired from the gut lumen. Maintenance of mucosal tolerance is critical, as evidenced by the inflammatory bowel disease (IBD)-like syndromes that occur in various cell or cytokine deficiencies affecting immunoregulation (115). However, inflammatory mediators and infections can also provide signals that “break” T cell tolerance in the mucosae. For example, the adoptive transfer of naive neoself antigen-specific CD8 cells to the iFABP (intestinal fatty-acid-binding protein promoter)-OVA transgenic mice described above is necessary and sufficient to initiate destruction of intestinal tissue in response to nonspecific inflammation induced

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by viral infection or TLR ligand stimulation (116). In the absence of such inflammatory mediators, transfer of the same population of neoself antigen-specific CD8 cells generates large numbers of activated T cells that enter the intestinal epithelium but do not cause tissue damage. Thus, the addition of inflammatory signals, even in the absence of added antigen, promotes a greater level of T cell activation that subsequently results in tissue pathology. Because the capacity of APC function within mucosal sites is responsive to environmental stimuli, changes in the outcome of coincident T cell (re)encounter with antigens can be induced (50, 106, 109, 116–118). Similar events may regulate CD4 T cell autoreactivity since normal bacterial flora are required for induction of colitis in models where CD4 T cells are the aggressors (119, 120). In these cases, it is unclear whether the “autoreactive” T cells are specific for intestinal selfantigens or are reactive with lumenal bacterial antigens, although there is experimental evidence in support of the latter (121). In either scenario, gut cytokine dysregulation (e.g., lack of anti-inflammatory cytokines such as IL-10 or TGF-β) may lead to defective control of T cell proliferation and activation with concomitant production of deleterious levels of proinflammatory cytokines that mediate bystander tissue damage. Similar to the oral route, administration of innocuous proteins to the lung via an aerosol or intranasally results in the induction of systemic tolerance. In the respiratory tract, it has been demonstrated that anti-inflammatory cytokines [e.g., IFNγ (85) or IL-10 (90)], regulatory T cells [including some populations of TCRγδ cells (85)], or specific populations of APCs [e.g., alveolar macrophages (71) or plasmacytoid DCs (99)] are involved in maintaining tolerance in the lung. All of these mechanisms likely contribute to some aspect of the tolerogenic state of the lung in healthy animals. An additional level of complexity in the lung is the observation that the distribution and function of DCs and other APCs in the respiratory tract is based on anatomical

location (45) and this may also apply to the intestinal mucosa.

T CELL MIGRATION TO MUCOSAL TISSUES Activated T Cell Migration to Mucosal Tissues In general, activation engenders properties to the T cells that promote their migration to nonlymphoid tissues. For example, the great majority of CD8 T cells, regardless of the secondary lymphoid tissue in which they are activated, upregulate a variety of adhesion molecules, such as CD11a and CD44, that are likely to participate in movement of these cells into multiple nonlymphoid tissues (22). Broadly expressed trafficking molecules such as these may be required but are insufficient on their own to promote entry into a particular tissue. For tissue-specific homing, specialized adhesion and chemokine receptors are required (122). CD8 effector T cell migration to the intestinal LP requires the α4β7 integrin (10, 123, 124), whose major counterreceptor is MadCAM (125). CD8 T cells lacking this integrin and responding to a systemic virus infection fail to enter the LP and consequently do not enter the IEL compartment (10). Expression of the β7 integrin is required for CD4+ regulatory T cells to enter the MLN but not to inhibit intestinal pathology in a murine model of colitis (126). Interruption of P-selectin ligand interactions also inhibits entry of effector CD4 T cells into the LP (124). Although naive β7−/− CD8 T cells enter the MLN, activated β7−/− CD8 T cells do not. This phenomenon may be the result of the use of L-selectin and CCR7 by naive T cells to enter MLN (127) while these molecules are downregulated by T cell activation, thereby increasing the relative importance of α4β7 for MLN entry. In contrast, most naive lymphocytes appear to require α4β7 to enter the PP. The second β7 integrin, αEβ7(CD103), is highly expressed by many mucosal T cells (128–130) and binds to E-cadherin (131,

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132). This integrin is not required for CD8 T cell migration to the intestine and also does not appear to be involved in retention of virus-specific effector or memory cells in the epithelium (10), although more rigorous testing is required to solidify this conclusion. However, the αEβ7 integrin is important for epithelial retention of autoreactive T cells in graft-versus-host disease and is involved in tissue destruction (133). Chemokines and their receptors are also important for lymphocyte migration to the intestinal mucosa. In particular, CCR9 (whose ligand TECK is expressed by IEC in the small but not the large intestine) is involved in T cell migration to the mucosa (134–136). Elegant studies have shown definitively that CCR9 expression by activated CD8 T cells is crucial to their ability to migrate to the intestinal epithelium (136, 137). However, it is not known whether CCR9 is required for activated T cell migration to the intestinal LP and whether CD4 T cells behave similarly. Although less is known regarding antigenspecific T cell migration to the lung, significant headway in this area has been recently made [for an excellent review see (138)]. Although the role of integrins in activated T cell migration to the lung is not fully understood, it is known that integrins are expressed by leukocytes, particularly those present within the lung airways (139), and that integrins are significantly involved during the effector phase of inflammatory responses within the respiratory tract (140–142). Similar to the gut, accumulation of lymphocytes in the BAL and lung LP as induced by challenge with aerosolized allergen is inhibited by interruption of α4-containing integrins (α4β1 and/or α4β7) or P-selectin, providing protection from allergic airway disease (142, 143). In these models, because T cells are initially primed by systemic immunization with allergen in adjuvant, the antigen-specific T cells are likely localized in the lung prior to treatment with the integrin-blocking reagents and challenge with aerosolized allergen. Thus, these integrins may well be necessary for ad-

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ditional T cell recruitment to the lung during the inflammatory response or they participate during the second hit within mucosal sites (see below). Another example is the collagenbinding α1β1 integrin (VLA-1), which is highly expressed by virus-specific primary and memory CD8 T cells in the lung airways following influenza virus infection (144). Although this integrin does not appear to be required for migration of CD8 T cells to the lung, VLA-1 blockade inhibits protection against secondary infection by an as-yet undefined mechanism. Similar to many intestinal T cells, effector T cells in the airways responding to respiratory virus infection or allergen challenge in allergic airway disease express the αEβ7 integrin (139, 145). Thus, expression of this adhesion molecule is linked to mucosal tissues where its ligand, E-cadherin, is expressed. The function of αEβ7 in the lung remains unclear, but in the gut may be important for retention of T cells and interaction with epithelial cells when antigen is present (133). The β2 integrin, CD11c, traditionally thought of as a DC marker, is also expressed by subsets of cytotoxic lung and gut LP T cells and IELs, but the impact of the expression of the CD11c molecule itself on T cell function is not known (75, 76). A novel mechanism of lymphocyte migration to the lung has recently been described involving leukotriene and prostaglandin receptors. CD4 T cells utilize the leukotriene B4 receptor BLT1 in early effector cell migration to the inflamed lung (146). Prostaglandin D2 is also involved in CD4 T cell migration, especially Th2-type cells, to the lung and the lung airways. PGD2 interacts with its receptor, DP1, expressed by lung epithelium, which in turn induces production of T cell-attracting chemokines. The chemokine receptors involved in CD4 Th2 effector migration to the lung include CCR3, CCR4, and CCR8. Thus, through a multitiered induction of chemoattractants, effector T cells are recruited to the lung. In murine models of asthma, such as allergic airway disease, initiation of mucosal disease requires a population

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of memory T cells capable of producing proinflammatory cytokines upon exposure to recall antigen within the respiratory tract [e.g., IFNγ to upregulate VCAM/ICAM expression by epithelial cells (148, 149)]. It is hypothesized that antigen-specific T cells enter the lung LP upon differentiation to effector cells during the primary response. In other models, it was shown that a primary immune response within the respiratory tract is induced by introduction of aerosolized antigen in the context of a TLR agonist, such as LPS, or proinflammatory cytokine, such as TNF (50, 109, 150). Adoptive transfer of effector T cells generated in vitro in conjunction with aerosolized antigen challenge is also sufficient to initiate the airway inflammatory response (151, 152). The overproduction of a wide variety of cytokines by lung epithelial cells, e.g., IL-4, IL-9, or IL-13 in naive mice, results in T cell recruitment to the lung and airways and spontaneous airway inflammation typical of asthma (143, 153, 154). Models of allergic intestinal disease have also been developed but the requirements for T cell migration to the intestinal mucosa in these systems have not been elucidated (155–157).

Imprinting of Tissue-Homing Properties Tissue-specific homing is a long-held concept suggesting that activated T cells preferentially home to the tissue in which they were originally primed (158). Recent results indicate that DCs derived from mucosal lymphoid sites (e.g., MLN and PP) preferentially induce mucosal homing molecules on the responding T cells (Figure 1) (137, 159, 160). Thus, activation of CD4 or CD8 T cells by MLN or PP DCs induces expression of α4β7 and CCR9. In contrast, DCs from the spleen or peripheral LN do not preferentially induce these molecules. Rather, LN draining the skin impart a skin-homing phenotype to the T cells. The vitamin A metabolite, retinoic acid (RA), has been implicated in imprinting intestinal tropism (α4β7 and CCR9 expression) to acti-

vated CD4 T cells, and DCs from MLN and PP express the enzymes required for production of RA from retinol (161). Whether imprinting is a feature of all LNdraining nonlymphoid tissues is unknown, and thus far induction of tissue-specific tropism of T cells migrating to the lung has not been described. Note also that initiation of an immune response in the secondary lymphoid tissues draining a mucosal site is not absolutely required for T cell migration to that site. For example, low-dose intravenous LM infection results in T cell priming nearly exclusively in the spleen, yet antigen-specific T cells migrate efficiently to the gut LP as well as to the lung (K.D. Klonowski, A.L. Marzo, K.J. Williams, S.-J. Lee, Q.-M. Pham & L. Lefranc¸ois, unpublished results). Influenza virus or Sendai virus infection of the lung also generates a primary and memory CD8 T cell response, albeit small, in the gut LP, whereas oral rotavirus infection induces primary CD8 T cells capable of migrating to the lung and liver (22). In general, activation of CD8 T cells, regardless of the priming site, imparts a transient ability to migrate to all nonlymphoid tissues. Whether the same is true for CD4 T cells has yet to be rigorously tested. This is not to say that priming in a mucosal site does not impart a preference for migration to mucosal effector sites, which in itself may enhance immune responses and perhaps memory generation within that tissue.

FUNCTIONAL REGULATION OF T CELL RESPONSES IN MUCOSAL EFFECTOR SITES: THE SECOND-HIT HYPOTHESIS Once primary activation of T cells occurs in LN-draining mucosae, the activated cells leave the LN and migrate to mucosal effector sites. Because effector T cells in mucosal tissues may exhibit distinct functional properties, a question arises as to the location where functional differentiation occurs.

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That is, are functional properties imparted during priming in secondary lymphoid organs or do changes occur as a result of entry into nonlymphoid tissues or residence in that tissue? The function or phenotype of effector or memory T cells entering tissue may be impinged upon by at least three events: (a) traversing endothelium which requires adhesion receptor engagement; (b) interaction with costimulators expressed by APCs or non-APCs (which may include TCR engagement with antigen); or (c) interaction with locally produced cytokines. These phenomena may be considered as a “second hit” that occurs following the initial priming event and results in functional modifications of the responding cells. Although endothelial cells may in some cases present antigen and express costimulators (162), no data are available that demonstrate a role for endothelium in mucosal T cell activation. In addition, the process of transendothelial migration, which may require engagement of selectins, integrins, and chemokine receptors (163), could functionally alter migrating T cells, although a direct demonstration of such effects on mucosal T cells is lacking. However, there is reasonable evidence that secondary costimulator signaling can occur upon entry of T cells into the lung or intestinal mucosa effector sites. For example, the response of antiviral CD8 T cells migrating into the gut LP is amplified by CD40/CD40L interactions (164). A recent report also shows that the CD27/CD70 costimulator pair enhances intestinal effector CD8 T cell responses to oral LM infection, apparently without affecting priming, although this was not directly examined (165). A CD70+ LP APC of nonhematopoietic origin is implicated in this process, although other CD70+ APCs could also be involved. Local cytokines can also affect T cells in the intestinal mucosa. Memory CD8 T cells migrating into the gut LP and IEL compartment upregulate αEβ7 and CD69 (166–168), molecules whose expression is upregulated by TGF-β and IFNα, respectively. TGF-β also

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promotes αEβ7 expression on incoming T cells in a model of graft-versus-host disease, and this integrin is involved in inducing IEC pathology (133). In the lung and the intestine, secondary costimulatory events as well as local cytokines play important roles in regulating T cell responses. For example, antiviral (LCMV)specific CD8 T cells migrating into the lung can alter their cytokine production from IFNγ to IL-5 when a concomitant Th2 response is under way (169) and allergic airway inflammation is reduced by a concomitant virus infection (170). Also, an enteric parasitic infection dampens the allergic response to a dietary allergen (171, 172). Costimulation in the parenchymal tissue following priming in the LN or other secondary lymphoid organs may also occur in the mucosae. For example, following systemic infection with vesicular stomatitis virus (VSV), the frequency of antigen-specific IL-5-producing CD4 T cells was fivefold greater than the frequency of IL4-producing cells specifically in the lung. Similar results were observed following sensitization with OVA/Alum in a murine model of allergic airway disease. This was in contrast to the frequency of IL-4 or IL-5 cytokine production by antigen-specific CD4 T cells in the spleen, which was equivalent in both systems. Production of IL-5, but not of IL-4, by the antiviral CD4 T cells was greatly inhibited in the lung and intestinal LP following blockade of the inducible costimulator (ICOS) (A.L. Marzo, L. Puddington & L. Lefranc¸ois, unpublished results). Moreover, ICOS is involved in regulating Th2 cytokine production during allergic airway disease, although the precise site or cell type that mediates this effect is unknown (173). Thus, there appear to be both positive and negative costimulators that are not necessarily involved in priming in LN or spleen, but that finetune the T cell response of effector cells upon entry to mucosal tissues. It also remains possible that DCs migrating from mucosal tissues to draining LN, which can be basal and constitutive or accelerated based on the

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character of the mucosal inflammatory response, express a tissue-specific array of costimulators capable of inducing a specific set of functional outcomes.

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MUCOSAL T CELL MEMORY Many of the T cells present in mucosal effector sites phenotypically resemble effector/memory cells. However, especially in the lung, a significant population of naive CD4 and CD8 T cells can be found within the parenchyma (S.C. Cose & L. Lefranc¸ois, unpublished results). Such cells are likely to be transient residents of the tissue (174), and this may be a mechanism for inducing or maintaining tolerance to tissue-specific antigens (175). For memory T cells, there are distinct requirements for migration into the lung LP versus the gut LP and the IEL compartment. In the lung, the presence of memory T cells in the parenchyma does not necessarily indicate their presence in the airways. For example, in normal unimmunized mice, memory phenotype CD4 and CD8 T cells are present in the lung LP but few lymphocytes are present in the airways. In addition, following systemic infection with VSV or LM, although substantial populations of antigen-specific memory cells are present in the lung parenchyma, few cells are found in the airways. In contrast, following pulmonary infection with influenza or Sendai virus, or induction of allergic airway disease, memory cells are present in the lung parenchyma as well as in the airways for several weeks after challenge (34, 35, 176). Many of the memory cells in the airways following respiratory virus infection express the early activation antigen CD69 (76, 177), suggesting recent encounter with antigen. Local inflammation appears to be needed for recruitment of memory T cells into the airways. Antigennonspecific memory T cells can be recruited to the airways by heterologous viral infections or intranasal instillation of TLR ligands such as CpG DNA (178, 179). Whether a similar phenomenon occurs with T cell migration into the intestinal epithelium is not known.

There are two general types of memory T cells based on phenotype and location (180, 181). Central memory cells (Tcm) are present primarily in lymph nodes and express homing molecules necessary for entry into that site including the selectin CD62L and the chemokine receptor CCR7. Effector memory cells (Tem) lack these molecules and reside primarily in nonlymphoid tissues. Both populations can be found in the blood and spleen, suggesting that each has the ability to migrate. However, there is significant phenotypic heterogeneity within each subtype even within nonlymphoid tissues (182), making function perhaps the most reliable indicator of memory cell subclass. That is, effector memory CD8 T cells in mouse and human express direct ex vivo lytic activity as compared to Tcm, whereas CD4 Tem exhibit increased effector cytokine production over Tcm (180, 183). There has also been significant discussion as to the interrelatedness of Tem and Tcm (184– 186), and recent evidence suggests that under normal circumstances Tem and Tcm represent distinct, noninterconvertible memory cell lineages, at least when phenotypic segregation is based on CD62L expression (187). The protective capability of each subset is also controversial, but the location of the infection or tumor is likely to dictate the functional relevance of each subset (188). Thus, whereas protection against the spleen-centric LCMV requires Tcm (185), lung Tem protect against respiratory virus infection (188). It makes teleological sense to link protective capabilities of each subset to its tissue of residence, perhaps as dictated by the tropism of a particular pathogen, rather than to assign protective function to one or the other of the lineages, which would necessarily limit the efficacy of recall responses. As discussed above, the imprinting of tissue-specific migratory abilities to effector cells occurs in secondary lymphoid tissues, such as the skin-draining LN or the small intestinal PP (159, 160). The resulting memory cells may retain these homing properties. Also, subsets of memory-phenotype

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human peripheral blood T cells expressing either mucosal or skin-homing molecules have been described. However, there appears to be plasticity in the process of imprinting in that memory cells expressing a nonmucosal pattern of trafficking molecules can be redirected to express a mucosal homing phenotype (189). This dynamic process suggests that migrating memory cells may modify their homing behavior depending on their location at the time of antigen reencounter. A remaining question is whether mucosal memory T cells exit the tissues and enter the blood stream and either home back to their tissue of origin or exhibit a less restricted homing pattern. Memory cells may exit tissues via the draining lymph, resulting in their eventual appearance in the blood. However, since effector T cells require CCR7 expression to exit tissues and move into the afferent lymph vessels (190, 191), it will be of interest to compare the ability of Tem versus Tcm to access draining lymph nodes of lung and intestine. The patterns of memory T cell migration to the mucosae have recently been studied using parabiosis (168). In this system, surgically joined mice with shared blood flow allow analysis of migration of blood-borne lymphocytes. CD8 and CD4 memory T cells raised by systemic infection of one mouse with VSV or LM rapidly equilibrate in the lymphoid tissues as well as in the lung LP and liver of the conjoined partner. In contrast, memory T cell entry into the gut LP and epithelium is highly restricted, with only small numbers of cells entering these sites over several weeks. Memory T cell migration into the intestinal mucosa, including the PP, requires β7 integrin expression by the circulating T cells. Entry of memory T cells into the intestinal mucosa results in upregulation of CD69, even in uninfected partner mice, indicating that CD69 upregulation is not obligately linked to recent encounter with antigen in this tissue. Still unclear is the tissue of origin of the migrating memory cells. Thus, a common pool of mobile memory cells may have the ability to enter multiple tissues. Alternatively, mem-

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ory T cells entering the lung may have originated in the partner lung, although why cells would enter the bloodstream only to return to their original location is unclear. There could also exist multiple pools of circulating memory cells, with subsets able to access either multiple or single tissues. In the intestine, the altered phenotype of the entering memory cells and the lack of such cells elsewhere suggest that memory T cells in the intestinal LP and epithelium are tissue-bound and do not exit the tissue, but this theory remains unproven. Similarly, airway memory cells appear to remain in that site rather than re-enter the lung LP (192). Finally, it remains to be examined whether memory T cell migration will be differentially affected when memory is raised against distinct pathogens or antigenic moieties. Thus, memory cells generated in response to infections restricted to mucosal tissues such as influenza virus in the lung or rotavirus in the intestine, or memory cells specific for chronic pathogens, may exhibit specialized migratory properties due to modifications at the level of the T cell, the APC, and/or the environmental milieu (e.g., infections or during chronic inflammatory disease).

CONCLUSIONS Mucosal T cells are essential to maintaining barrier function of a vast surface area. Consequently, mucosal T cells must be functionally diverse, acquiring the ability to combat a multitude of phylogenetically distinct organisms while also providing homeostatic control over dynamic inflammatory processes. Although substantial progress has been made in understanding mucosal T cell responses, many questions remain regarding the molecular events controlling their trafficking and, in particular, the differentiation events leading to the emergence of effector functions. Further analysis of the mucosal immune system is critical to our ability to deliver efficacious mucosal vaccines as well as to intervene to prevent or reverse tissue damage during deleterious autoimmune or other pathogenic conditions.

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SUMMARY POINTS 1. The anatomy of the mucosal tissues orchestrates immunity: Distinct inductive sites (lymph nodes, PP, BALT) and effector sites (LP, epithelium, airways) work in concert to provide effective local immunity. Unregulated T cell inflammation, however, can induce pathology (e.g., IBD, asthma).

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2. APCs acquire antigen in parenchymal tissue and migrate to inductive sites via multiple mechanisms dependent on the source of antigen (e.g., characteristics of pathogen, self-antigen, location of antigen/infectious organism). 3. Tolerance or immunity results from APC-T cell interaction in the mucosal LN or PP. The choice depends in part on the status of the APC—resting APCs bearing self or innocuous antigens drive tolerance induction, whereas activated APCs drive immunity. 4. T cell responses in mucosal sites can influence the environment of antigen presentation within that site. 5. Naive, effector, and memory T cell migration to mucosal tissues is a multitiered event requiring distinct adhesion molecules for entry into lung versus intestine. Imprinting of T cells by mucosal DCs results in acquisition of tissue-specific homing abilities. 6. Mucosal T cells may be acted upon by secondary costimulatory events upon entry into the tissue, thereby providing tissue-specific tuning of effector functions. 7. Memory cells comprise a large proportion of mucosal T cells and exhibit functional and phenotypic characteristics unique to their location.

ACKNOWLEDGMENTS We thank the members of our laboratories for their dedication to deciphering the concepts discussed here. Our work is funded by the National Institutes of Health and the American Lung Association of Connecticut. We regret any errors of omission in referencing as a result of space limitations.

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Contents

Annual Review of Immunology Volume 24, 2006

Annu. Rev. Immunol. 2006.24:681-704. Downloaded from arjournals.annualreviews.org by INSERM-multi-site account on 03/28/07. For personal use only.

Frontispiece Jack L. Strominger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x The Tortuous Journey of a Biochemist to Immunoland and What He Found There Jack L. Strominger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Osteoimmunology: Interplay Between the Immune System and Bone Metabolism Matthew C. Walsh, Nacksung Kim, Yuho Kadono, Jaerang Rho, Soo Young Lee, Joseph Lorenzo, and Yongwon Choi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33 A Molecular Perspective of CTLA-4 Function Wendy A. Teft, Mark G. Kirchhof, and Joaquín Madrenas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65 Transforming Growth Factor-β Regulation of Immune Responses Ming O. Li, Yisong Y. Wan, Shomyseh Sanjabi, Anna-Karin L. Robertson, and Richard A. Flavell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99 The Eosinophil Marc E. Rothenberg and Simon P. Hogan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 147 Human T Cell Responses Against Melanoma Thierry Boon, Pierre G. Coulie, Benoît J. Van den Eynde, and Pierre van der Bruggen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175 FOXP3: Of Mice and Men Steven F. Ziegler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209 HIV Vaccines Andrew J. McMichael p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227 Natural Killer Cell Developmental Pathways: A Question of Balance James P. Di Santo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 257 Development of Human Lymphoid Cells Bianca Blom and Hergen Spits p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287 Genetic Disorders of Programmed Cell Death in the Immune System Nicolas Bidère, Helen C. Su, and Michael J. Lenardo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321

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Genetic Analysis of Host Resistance: Toll-Like Receptor Signaling and Immunity at Large Bruce Beutler, Zhengfan Jiang, Philippe Georgel, Karine Crozat, Ben Croker, Sophie Rutschmann, Xin Du, and Kasper Hoebe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353 Multiplexed Protein Array Platforms for Analysis of Autoimmune Diseases Imelda Balboni, Steven M. Chan, Michael Kattah, Jessica D. Tenenbaum, Atul J. Butte, and Paul J. Utz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 391 How TCRs Bind MHCs, Peptides, and Coreceptors Markus G. Rudolph, Robyn L. Stanfield, and Ian A. Wilson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 419 Annu. Rev. Immunol. 2006.24:681-704. Downloaded from arjournals.annualreviews.org by INSERM-multi-site account on 03/28/07. For personal use only.

B Cell Immunobiology in Disease: Evolving Concepts from the Clinic Flavius Martin and Andrew C. Chan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467 The Evolution of Adaptive Immunity Zeev Pancer and Max D. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 497 Cooperation Between CD4+ and CD8+ T Cells: When, Where, and How Flora Castellino and Ronald N. Germain p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519 Mechanism and Control of V(D)J Recombination at the Immunoglobulin Heavy Chain Locus David Jung, Cosmas Giallourakis, Raul Mostoslavsky, and Frederick W. Alt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 541 A Central Role for Central Tolerance Bruno Kyewski and Ludger Klein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 571 Regulation of Th2 Differentiation and Il4 Locus Accessibility K. Mark Ansel, Ivana Djuretic, Bogdan Tanasa, and Anjana Rao p p p p p p p p p p p p p p p p p p p p p p p 607 Diverse Functions of IL-2, IL-15, and IL-7 in Lymphoid Homeostasis Averil Ma, Rima Koka, and Patrick Burkett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 657 Intestinal and Pulmonary Mucosal T Cells: Local Heroes Fight to Maintain the Status Quo Leo Lefrançois and Lynn Puddington p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 681 Determinants of Lymphoid-Myeloid Lineage Diversification Catherine V. Laiosa, Matthias Stadtfeld, and Thomas Graf p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 705 GP120: Target for Neutralizing HIV-1 Antibodies Ralph Pantophlet and Dennis R. Burton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 739 Compartmentalized Ras/MAPK Signaling Adam Mor and Mark R. Philips p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 771

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