Hallmarks of Tissue-Resident Lymphocytes

Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα+ IELs), and tissue-resident memory T (TRM) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs. Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα+ IELs), and tissue-resident memory T (TRM) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs. From an evolutionary perspective, the mammalian adaptive immune system is the pinnacle of metazoan immune defenses in terms of its complexity and potential for molecular specificity. In contrast to innate immune systems, which rely on germline-encoded receptors to recognize stereotypic motifs associated with broad classes of pathogens, the hallmark of adaptive immunity is the generation of near-limitless antigen receptor diversity through somatic recombination, which in turn provides the foundation for immunological memory through the differentiation, expansion, and persistence of long-lived antigen-specific lymphocytes (Janeway, 1989Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb. Symp. Quant. Biol. 1989; 54: 1-13Crossref PubMed Google Scholar, Medzhitov and Janeway, 2000Medzhitov R. Janeway Jr., C. Innate immunity.N. Engl. J. Med. 2000; 343: 338-344Crossref PubMed Scopus (1467) Google Scholar, Medzhitov, 2009Medzhitov R. Approaching the asymptote: 20 years later.Immunity. 2009; 30: 766-775Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). Although they serve as direct effectors of immunity by elaborating cytotoxic function and antibody production, cells of the adaptive immune system act foremost as principal controllers, amplifying or limiting the responses of diverse cell types through positive and negative feedback loops. At a basic level, the mammalian adaptive immune response is initiated by antigen-presenting cells (APCs) migrating from the site of infection to the draining lymph node to present captured microbial antigens to naive T cells, which constitutively recirculate between lymph nodes to survey presented antigens. When a naive T cell encounters its cognate antigen, it undergoes clonal expansion, a process that takes several days and results in the differentiation of both effector and memory T cells. While effector T cells home to the site of the primary infection and contribute to pathogen clearance, circulating memory T cells persist and are poised to mount a superior response to secondary infection. Teleologically, this efficient system of naive lymphocyte recirculation is necessitated by the minute frequencies at which individual lymphocyte clones are present, such that a given clone, incapable of being in all anatomical locations at once, instead patrols strategically positioned lymph nodes, which collect information on the statuses of tissues and organs—i.e., the antigenic landscape (Jenkins et al., 2010Jenkins M.K. Chu H.H. McLachlan J.B. Moon J.J. On the composition of the preimmune repertoire of T cells specific for Peptide-major histocompatibility complex ligands.Annu. Rev. Immunol. 2010; 28: 275-294Crossref PubMed Scopus (103) Google Scholar, Maryanski et al., 1996Maryanski J.L. Jongeneel C.V. Bucher P. Casanova J.L. Walker P.R. Single-cell PCR analysis of TCR repertoires selected by antigen in vivo: a high magnitude CD8 response is comprised of very few clones.Immunity. 1996; 4: 47-55Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, von Andrian and Mackay, 2000von Andrian U.H. Mackay C.R. T-cell function and migration. Two sides of the same coin.N. Engl. J. Med. 2000; 343: 1020-1034Crossref PubMed Scopus (1089) Google Scholar). In contrast to this classical view of adaptive lymphocytes, studies in the last 10 years have led to a characterization of lymphocyte populations that are non-recirculating residents of non-lymphoid tissues and organs. These populations include tissue-resident memory T cells (TRM); “unconventional” T cells such as invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and intestinal intraepithelial lymphocytes (IELs); and the emerging family of innate lymphoid cells (ILCs) (Artis and Spits, 2015Artis D. Spits H. The biology of innate lymphoid cells.Nature. 2015; 517: 293-301Crossref PubMed Scopus (493) Google Scholar, Clark, 2015Clark R.A. Resident memory T cells in human health and disease.Sci. Transl. Med. 2015; 7: 269rv1Crossref PubMed Scopus (107) Google Scholar, Eberl et al., 2015Eberl G. Colonna M. Di Santo J.P. McKenzie A.N.J. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.Science. 2015; 348: aaa6566Crossref PubMed Scopus (231) Google Scholar, Godfrey et al., 2015Godfrey D.I. Uldrich A.P. McCluskey J. Rossjohn J. Moody D.B. The burgeoning family of unconventional T cells.Nat. Immunol. 2015; 16: 1114-1123Crossref PubMed Scopus (180) Google Scholar, Schenkel and Masopust, 2014Schenkel J.M. Masopust D. Tissue-resident memory T cells.Immunity. 2014; 41: 886-897Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). These tissue-resident lymphocytes span the innate-adaptive continuum but nonetheless share a number of particular features pertaining to their tissue-resident functions. In this Review, we will discuss the properties and functions of lymphocytes residing in non-lymphoid tissues. Just as manipulation of lymphocyte recirculation has resulted in effective therapies for autoimmune diseases such as multiple sclerosis (Pelletier and Hafler, 2012Pelletier D. Hafler D.A. Fingolimod for multiple sclerosis.N. Engl. J. Med. 2012; 366: 339-347Crossref PubMed Scopus (189) Google Scholar, Ransohoff, 2007Ransohoff R.M. Natalizumab for multiple sclerosis.N. Engl. J. Med. 2007; 356: 2622-2629Crossref PubMed Scopus (186) Google Scholar, von Andrian and Engelhardt, 2003von Andrian U.H. Engelhardt B. Alpha4 integrins as therapeutic targets in autoimmune disease.N. Engl. J. Med. 2003; 348: 68-72Crossref PubMed Scopus (0) Google Scholar), a better understanding of tissue-resident lymphocytes may reveal new cellular mechanisms of organ dysfunction in a multitude of inflammatory, infectious, and neoplastic processes and suggest novel approaches for their treatment. The discovery of tissue-resident lymphocytes owes to experimental approaches that allow for discrimination of circulating and tissue-resident populations. One of the most commonly used means of assessing tissue residency is parabiosis, whereby two congenic mice expressing distinct allelic markers of hematopoietic cells are surgically conjoined through adjacent skin, such that they develop a shared anastomotic circulation (Wright et al., 2001Wright D.E. Wagers A.J. Gulati A.P. Johnson F.L. Weissman I.L. Physiological migration of hematopoietic stem and progenitor cells.Science. 2001; 294: 1933-1936Crossref PubMed Scopus (664) Google Scholar). This approach pinpoints tissue-resident cell populations by their exclusive expression of the host congenic marker, in contrast to actively recirculating cells and their progeny, which exhibit both host and donor markers in equal proportion. It must be noted that the extent and kinetics of equilibration between circulating cells originating from the two parabionts is dependent on the turnover rate of a given cell subset. While two populations may be similarly replaced by circulating precursors, the longer-lived population is replaced more slowly and, thus, appears to be tissue-resident to a greater extent. Furthermore, failure of a population to exchange in parabiosis does not imply that cells of that population are sessile and static. For example, in the absence of inflammation, Langerhans cells remain overwhelmingly host-derived in parabiotic mice (Merad et al., 2002Merad M. Manz M.G. Karsunky H. Wagers A. Peters W. Charo I. Weissman I.L. Cyster J.G. Engleman E.G. Langerhans cells renew in the skin throughout life under steady-state conditions.Nat. Immunol. 2002; 3: 1135-1141Crossref PubMed Scopus (665) Google Scholar), although they migrate continuously and unidirectionally from the epidermis to skin-draining lymph nodes (Bajaña et al., 2012Bajaña S. Roach K. Turner S. Paul J. Kovats S. IRF4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation.J. Immunol. 2012; 189: 3368-3377Crossref PubMed Scopus (75) Google Scholar, Ohl et al., 2004Ohl L. Mohaupt M. Czeloth N. Hintzen G. Kiafard Z. Zwirner J. Blankenstein T. Henning G. Förster R. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.Immunity. 2004; 21: 279-288Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Tomura et al., 2014Tomura M. Hata A. Matsuoka S. Shand F.H.W. Nakanishi Y. Ikebuchi R. Ueha S. Tsutsui H. Inaba K. Matsushima K. et al.Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes.Sci. Rep. 2014; 4: 6030Crossref PubMed Scopus (45) Google Scholar). Additionally, imaging studies have shown that liver-resident iNKT cells, epidermis-resident CD8+ TRM cells, and intestine-resident ILCs exhibit dynamic behavior within their respective tissues (Gebhardt et al., 2011Gebhardt T. Whitney P.G. Zaid A. Mackay L.K. Brooks A.G. Heath W.R. Carbone F.R. Mueller S.N. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells.Nature. 2011; 477: 216-219Crossref PubMed Scopus (262) Google Scholar, Geissmann et al., 2005Geissmann F. Cameron T.O. Sidobre S. Manlongat N. Kronenberg M. Briskin M.J. Dustin M.L. Littman D.R. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids.PLoS Biol. 2005; 3: e113Crossref PubMed Scopus (379) Google Scholar, Mackley et al., 2015Mackley E.C. Houston S. Marriott C.L. Halford E.E. Lucas B. Cerovic V. Filbey K.J. Maizels R.M. Hepworth M.R. Sonnenberg G.F. et al.CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes.Nat. Commun. 2015; 6: 5862Crossref PubMed Google Scholar, Pearson et al., 2016Pearson C. Thornton E.E. McKenzie B. Schaupp A.-L. Huskens N. Griseri T. West N. Tung S. Seddon B.P. Uhlig H.H. Powrie F. ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.eLife. 2016; 5: 1-21Crossref Google Scholar, Zaid et al., 2014Zaid A. Mackay L.K. Rahimpour A. Braun A. Veldhoen M. Carbone F.R. Manton J.H. Heath W.R. Mueller S.N. Persistence of skin-resident memory T cells within an epidermal niche.Proc. Natl. Acad. Sci. USA. 2014; 111: 5307-5312Crossref PubMed Scopus (94) Google Scholar) but self-renew locally and are not replaced by circulating precursors (Gasteiger et al., 2015Gasteiger G. Fan X. Dikiy S. Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (183) Google Scholar, Jiang et al., 2012Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (373) Google Scholar, Thomas et al., 2011Thomas S.Y. Scanlon S.T. Griewank K.G. Constantinides M.G. Savage A.K. Barr K.A. Meng F. Luster A.D. Bendelac A. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions.J. Exp. Med. 2011; 208: 1179-1188Crossref PubMed Scopus (92) Google Scholar). Thus, cell tracking and imaging approaches offer an essential complement to the “10,000-foot view” provided by parabiosis. The mobile or sessile “styles” of tissue residency, and signal-dependent waves of migration to and from the tissue, have been elucidated through methodologies such as photo-switchable or constitutive cell tagging, direct visualization of cellular behavior using intravital imaging, and analysis of tissue explants or transplants into congenically marked mice. A combination of these approaches has revealed that a variety of tissue-resident lymphocytes, representing the innate and adaptive branches of immunity, differ in their distribution in non-lymphoid tissues yet exhibit common “innate”-like properties. These tissue-resident lymphocytes represent an integral part of a network of cells whose connections and hierarchy are poorly understood. However, it is reasonable to assume that they act as sensors of perturbed tissue integrity stemming from infection, injury, and potentially other forms of deviation from the homeostatic norm. In parallel to the role of their circulating counterparts in amplifying or suppressing innate immunity, tissue-resident lymphocytes likely support the functioning of non-lymphoid tissues by serving as sentinels of tissue integrity, recruiters of bloodborne reinforcements, and amplifiers of homeostatic mechanisms through feedback on parenchymal cells and non-lymphoid accessory cells (e.g., macrophages, fibroblasts, and endothelial cells) (Figure 1) (Medzhitov, 2008Medzhitov R. Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435Crossref PubMed Scopus (2086) Google Scholar). Below, we will briefly review features of innate and adaptive tissue-resident lymphocytes and discuss experimental observations supporting this hypothetical model. Toward the “innate”-most end of the innate-adaptive spectrum are ILCs, a diverse family of lymphocytes, including natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and the “helper-like” ILCs. Like other lymphocytes, all ILCs develop from the common lymphoid progenitor. Helper-like ILCs develop through a common helper-like ILC precursor (ChILP) shared with LTi but not NK cells and, subsequently, through an intermediate expressing transcription factor PLZF with only helper-like ILC potential (Constantinides et al., 2015Constantinides M.G. Gudjonson H. McDonald B.D. Ishizuka I.E. Verhoef P.A. Dinner A.R. Bendelac A. PLZF expression maps the early stages of ILC1 lineage development.Proc. Natl. Acad. Sci. USA. 2015; 112: 5123-5128Crossref PubMed Scopus (56) Google Scholar, Constantinides et al., 2014Constantinides M.G. McDonald B.D. Verhoef P.A. Bendelac A. A committed precursor to innate lymphoid cells.Nature. 2014; 508: 397-401Crossref PubMed Scopus (310) Google Scholar, Klose et al., 2014bKlose C.S.N. Flach M. Möhle L. Rogell L. Hoyler T. Ebert K. Fabiunke C. Pfeifer D. Sexl V. Fonseca-Pereira D. et al.Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.Cell. 2014; 157: 340-356Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, Wong et al., 2012Wong S.H. Walker J.A. Jolin H.E. Drynan L.F. Hams E. Camelo A. Barlow J.L. Neill D.R. Panova V. Koch U. et al.Transcription factor RORα is critical for nuocyte development.Nat. Immunol. 2012; 13: 229-236Crossref PubMed Scopus (320) Google Scholar). Long-term parabiosis experiments suggested that ILC and NK subsets residing in the non-lymphoid tissues and secondary lymphoid organs of adult mice are likely maintained through self-renewal with minimal contribution from hematogenous precursors under physiologic and inflammatory conditions (Gasteiger et al., 2015Gasteiger G. Fan X. Dikiy S. Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (183) Google Scholar, Peng et al., 2013Peng H. Jiang X. Chen Y. Sojka D.K. Wei H. Gao X. Sun R. Yokoyama W.M. Tian Z. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation.J. Clin. Invest. 2013; 123: 1444-1456Crossref PubMed Scopus (206) Google Scholar, Sojka et al., 2014Sojka D.K. Plougastel-Douglas B. Yang L. Pak-Wittel M.A. Artyomov M.N. Ivanova Y. Zhong C. Chase J.M. Rothman P.B. Yu J. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.eLife. 2014; 3: e01659Crossref PubMed Scopus (199) Google Scholar). Consistent with these findings, distinct features have been reported for salivary-gland-resident NK cells and ILCs with the key properties of the latter coordinately evolving with the development of their “home” organ (i.e., salivary gland) (Cortez et al., 2014Cortez V.S. Fuchs A. Cella M. Gilfillan S. Colonna M. Cutting edge: Salivary gland NK cells develop independently of Nfil3 in steady-state.J. Immunol. 2014; 192: 4487-4491Crossref PubMed Scopus (83) Google Scholar; M. Colonna, personal communication). Likewise, mature ILCs appear in the lung as early as day 8 of postnatal life, and intestinal ILCs appear to derive from a precursor present early in life (Bando et al., 2015Bando J.K. Liang H.-E. Locksley R.M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine.Nat. Immunol. 2015; 16: 153-160Crossref PubMed Scopus (57) Google Scholar, Nussbaum et al., 2013Nussbaum J.C. Van Dyken S.J. von Moltke J. Cheng L.E. Mohapatra A. Molofsky A.B. Thornton E.E. Krummel M.F. Chawla A. Liang H.-E. Locksley R.M. Type 2 innate lymphoid cells control eosinophil homeostasis.Nature. 2013; 502: 245-248Crossref PubMed Scopus (335) Google Scholar). Lending further support to the notion that ILCs serve important homeostatic functions in support of organs and tissues, the first characterized subset of ILC with a defined function were RORγt and lymphotoxin-expressing LTi cells essential for the organogenesis of lymph nodes and Peyer’s patches (Adachi et al., 1997Adachi S. Yoshida H. Kataoka H. Nishikawa S. Three distinctive steps in Peyer’s patch formation of murine embryo.Int. Immunol. 1997; 9: 507-514Crossref PubMed Scopus (156) Google Scholar, Eberl et al., 2004Eberl G. Marmon S. Sunshine M.-J. Rennert P.D. Choi Y. Littman D.R. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.Nat. Immunol. 2004; 5: 64-73Crossref PubMed Scopus (600) Google Scholar, Kelly and Scollay, 1992Kelly K.A. Scollay R. Seeding of neonatal lymph nodes by T cells and identification of a novel population of CD3-CD4+ cells.Eur. J. Immunol. 1992; 22: 329-334Crossref PubMed Google Scholar, Mebius et al., 1997Mebius R.E. Rennert P. Weissman I.L. Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells.Immunity. 1997; 7: 493-504Abstract Full Text Full Text PDF PubMed Google Scholar, Sun et al., 2000Sun Z. Unutmaz D. Zou Y.R. Sunshine M.J. Pierani A. Brenner-Morton S. Mebius R.E. Littman D.R. Requirement for RORgamma in thymocyte survival and lymphoid organ development.Science. 2000; 288: 2369-2373Crossref PubMed Scopus (507) Google Scholar). Lacking classical antigen receptors, ILCs are instead activated by cytokines, whereas NK cells are additionally stimulated through activating receptors such as NKG2D and Ly49H, or through a receptor for the immunoglobulin constant region (FcγRIII/CD16). Mirroring the T-helper polarization of conventional CD4+ T cells, helper-like ILCs can be subdivided into types 1, 2, and 3 (ILC1, ILC2, and ILC3) based on differential expression of the lineage-specifying transcription factors T-bet, GATA-3, and RORγt (respectively) and production of the corresponding effector cytokines interferon-γ (ILC1), IL-5 and IL-13 (ILC2), and IL-17 (ILC3) (Artis and Spits, 2015Artis D. Spits H. The biology of innate lymphoid cells.Nature. 2015; 517: 293-301Crossref PubMed Scopus (493) Google Scholar, Eberl et al., 2015Eberl G. Colonna M. Di Santo J.P. McKenzie A.N.J. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.Science. 2015; 348: aaa6566Crossref PubMed Scopus (231) Google Scholar). Besides producing cytokines that orchestrate and amplify antimicrobial defenses, ILCs also elaborate soluble factors that promote tissue maintenance. Different ILC subsets respond to the pro-inflammatory cytokine IL-23 or the alarmin IL-33 by producing tissue-protective factors IL-22 or amphiregulin, respectively (Cella et al., 2009Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K.M. Doherty J.M. Mills J.C. Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (750) Google Scholar, Monticelli et al., 2015Monticelli L.A. Osborne L.C. Noti M. Tran S.V. Zaiss D.M.W. Artis D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions.Proc. Natl. Acad. Sci. USA. 2015; 112: 10762-10767Crossref PubMed Scopus (303) Google Scholar, Monticelli et al., 2011Monticelli L.A. Sonnenberg G.F. Abt M.C. Alenghat T. Ziegler C.G.K. Doering T.A. Angelosanto J.M. Laidlaw B.J. Yang C.Y. Sathaliyawala T. et al.Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.Nat. Immunol. 2011; 12: 1045-1054Crossref PubMed Scopus (687) Google Scholar, Sanos et al., 2009Sanos S.L. Bui V.L. Mortha A. Oberle K. Heners C. Johner C. Diefenbach A. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.Nat. Immunol. 2009; 10: 83-91Crossref PubMed Scopus (499) Google Scholar). In contrast to ILCs, “unconventional” or “innate-like” T cells express T cell receptors (TCRs) of limited diversity, which recognize antigens in the context of non-classical, non-polymorphic MHC-like molecules, or independently of MHC-related presenting molecules altogether (Godfrey et al., 2015Godfrey D.I. Uldrich A.P. McCluskey J. Rossjohn J. Moody D.B. The burgeoning family of unconventional T cells.Nat. Immunol. 2015; 16: 1114-1123Crossref PubMed Scopus (180) Google Scholar). Lymphocytes belonging to this group include αβTCR-expressing iNKT, MAIT, and γδ T cells. iNKT cells express an invariant TCRα chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a TCRβ chain of limited diversity (Brennan et al., 2013Brennan P.J. Brigl M. Brenner M.B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions.Nat. Rev. Immunol. 2013; 13: 101-117Crossref PubMed Scopus (343) Google Scholar, Salio et al., 2014Salio M. Silk J.D. Jones E.Y. Cerundolo V. Biology of CD1- and MR1-restricted T cells.Annu. Rev. Immunol. 2014; 32: 323-366Crossref PubMed Scopus (108) Google Scholar). Unlike most αβTCRs, iNKT TCRs recognize glycolipid antigens presented by the MHC class I-like molecule CD1d (Bendelac et al., 1994Bendelac A. Killeen N. Littman D.R. Schwartz R.H. A subset of CD4+ thymocytes selected by MHC class I molecules.Science. 1994; 263: 1774-1778Crossref PubMed Google Scholar, Bendelac et al., 1995Bendelac A. Lantz O. Quimby M.E. Yewdell J.W. Bennink J.R. Brutkiewicz R.R. CD1 recognition by mouse NK1+ T lymphocytes.Science. 1995; 268: 863-865Crossref PubMed Google Scholar). Functionally, iNKT cells can be activated by potent bacterial ligands, such as cell wall sphingolipids from Sphingomonas, Borrelia, or Streptococcus (Kinjo et al., 2006Kinjo Y. Tupin E. Wu D. Fujio M. Garcia-Navarro R. Benhnia M.R.-E.-I. Zajonc D.M. Ben-Menachem G. Ainge G.D. Painter G.F. et al.Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria.Nat. Immunol. 2006; 7: 978-986Crossref PubMed Scopus (0) Google Scholar, Kinjo et al., 2011Kinjo Y. Illarionov P. Vela J.L. Pei B. Girardi E. Li X. Li Y. Imamura M. Kaneko Y. Okawara A. et al.Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.Nat. Immunol. 2011; 12: 966-974Crossref PubMed Scopus (0) Google Scholar, Sriram et al., 2005Sriram V. Du W. Gervay-Hague J. Brutkiewicz R.R. Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells.Eur. J. Immunol. 2005; 35: 1692-1701Crossref PubMed Scopus (0) Google Scholar). They can also sense changes in host lipid metabolism through recognition of transiently expressed, less potent, rare, or unstable endogenous lipids, a number of which have been proposed (Brennan et al., 2011Brennan P.J. Tatituri R.V.V. Brigl M. Kim E.Y. Tuli A. Sanderson J.P. Gadola S.D. Hsu F.-F. Besra G.S. Brenner M.B. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals.Nat. Immunol. 2011; 12: 1202-1211Crossref PubMed Scopus (215) Google Scholar, Brennan et al., 2014Brennan P.J. Tatituri R.V.V. Heiss C. Watts G.F.M. Hsu F.-F. Veerapen N. Cox L.R. Azadi P. Besra G.S. Brenner M.B. Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction.Proc. Natl. Acad. Sci. USA. 2014; 111: 13433-13438Crossref PubMed Scopus (0) Google Scholar, Facciotti et al., 2012Facciotti F. Ramanjaneyulu G.S. Lepore M. Sansano S. Cavallari M. Kistowska M. Forss-Petter S. Ni G. Colone A. Singhal A. et al.Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus.Nat. Immunol. 2012; 13: 474-480Crossref PubMed Scopus (116) Google Scholar, Kain et al., 2015Kain L. Costanzo A. Webb B. Holt M. Bendelac A. Savage P.B. Teyton L. Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides.Mol. Immunol. 2015; 68: 94-97Crossref PubMed Scopus (0) Google Scholar, Zhou et al., 2004Zhou D. Mattner J. Cantu 3rd, C. Schrantz N. Yin N. Gao Y. Sagiv Y. Hudspeth K. Wu Y.-P. Yamashita T. et al.Lysosomal glycosphingolipid recognition by NKT cells.Science. 2004; 306: 1786-1789Crossref PubMed Scopus (770) Google Scholar). This endogenous lipid sensing, which may in fact be the dominant mode of iNKT cell activation in vivo, allows iNKT cells to indirectly detect the breach of tissue integrity resulting from infection with viruses, fungi, and bacteria like Salmonella typhimurium, which lack potent agonist ligands (Cohen et al., 2011Cohen N.R. Tatituri R.V.V. Rivera A. Watts G.F.M. Kim E.Y. Chiba A. Fuchs B.B. Mylonakis E. Besra G.S. Levitz S.M. et al.Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi.Cell Host Microbe. 2011; 10: 437-450Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Mattner et al., 2005Mattner J. Debord K.L. Ismail N. Goff R.D. Cantu 3rd, C. Zhou D. Saint-Mezard P. Wang V. Gao Y. Yin N. et al.Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.Nature. 2005; 434: 525-529Crossref PubMed Scopus (859) Google Scholar). As with ILCs, NKT cell subsets analogous to TH1, TH2, and TH17 conventional T cells have been described. These subsets express the corresponding cytokines and transcriptional regulators of their T-helper counterparts and have been shown to localize to different tissues (Constantinides and Bendelac, 2013Constantinides M.G. Bendelac A. Transcriptional regulation of the NKT cell lineage.Curr. Opin. Immunol. 2013; 25: 161-167Crossref PubMed Scopus (120) Google Scholar, Coquet et al., 2008Coquet J.M. Chakravarti S. Kyparissoudis K. McNab F.W. Pitt L.A. McKenzie B.S. Berzins S.P. Smyth M.J. Godfrey D.I. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population.Proc. Natl. Acad. Sci. USA. 2008; 105: 11287-11292Crossref PubMed Scopus (0) Google Scholar, Lee et al., 2013Lee Y.J. Holzapfel K.L. Zhu J. Jameson S.C. Hogquist K.A. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells.Nat. Immunol. 2013; 14: 1146-1154Crossref PubMed Scopus (204) Google Scholar, Lee et al., 2015bLee Y.J. Wang H. Starrett G.J. Phuong V. Jameson S.C. Hogquist K.A. et al.Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response.Immunity. 2015; 43: 566-578Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, Michel et al., 2007Michel M.-L. Keller A.C. Paget C. Fujio M. Trottein F. Savage P.B. Wong C.-H. Schneider E. Dy M. Leite-de-Moraes M.C. Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia.J. Exp. Med. 2007; 204: 995-1001Crossref PubMed Scopus (0) Google Scholar, Watarai et al., 2012Watarai H. Sekine-Kondo E. Shigeura T. Motomura Y. Yasuda T. Satoh R. Yoshida H. Kubo M. Kawamoto H. Koseki H. Taniguchi M. Development and function of invariant natural killer T cells producing T(h)2- and T(h)17-cytokines.PLoS Biol. 2012; 10: e1001255Crossref PubMed Scopus (112) Google Scholar). Like iNKT cells, MAIT cells express a semi-invariant TCR combining a unique TCRα chain (Vα19-Jα33 in mice, Vα7.2