Key Points
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Whereas peptide–MHC complexes are the usual model for technology development focused on T cells, the discovery of lipids and non-lipid small molecules presented by CD1 and MHC class I-related protein (MR1) proteins expands the range of physiological antigens for human T cell responses.
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The human CD1 system consists of four antigen-presenting molecules, each with a different cell biological function. Most prior work on this system has focused on CD1d recognition by natural killer T (NKT) cells, but newly developed tetramers comprised of human CD1a, CD1b or CD1c molecules have created an opportunity to measure T cell function ex vivo in disease states.
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Many bacteria and fungi produce vitamin B metabolites (modified ribityl lumazines and ribityl pyrimidines), some of which can covalently bind in the A′ pocket of MR1 molecules and activate mucosal-associated invariant T (MAIT) cells.
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Whereas antigen-presenting cells trim large proteins into peptide antigens to fit the MHC groove, CD1 antigen processing starts with lipids that mostly match the CD1 cleft volume. Lipid antigens that are smaller than the cleft bind concomitantly with spacer lipids, and larger lipids are thought to protrude from the interior of CD1 proteins through accessory portals.
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Peptides span broadly across both sides of the MHC antigen display platform. Lipids bound to CD1 enter the T cell receptor (TCR) contact platform from the right side. This mode of binding creates a situation in which TCRs can predominantly contact CD1 protein or lipid, depending on whether the TCR takes a right-sided or left-sided approach.
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An unexpected mechanism for T cell autoreactivity was recently discovered in which a TCR binds directly to CD1a rather than to lipids carried in the cleft.
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Cellular CD1a proteins bind certain lipids with large head groups that disrupt the surface of CD1a. Such non-permissive ligands act by interfering with TCR contact to CD1a.
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NKT cells and MAIT cells are defined by TCRs that are nearly identical in all humans, and they bind CD1d and MR1 antigen-presenting molecules that are also nearly the same in all humans. New studies show that such invariant TCRs exist in the CD1b system and might be common in the human TCR repertoire.
Abstract
The antigen-presenting molecules CD1 and MHC class I-related protein (MR1) display lipids and small molecules to T cells. The antigen display platforms in the four CD1 proteins are laterally asymmetrical, so that the T cell receptor (TCR)-binding surfaces are comprised of roofs and portals, rather than the long grooves seen in the MHC antigen-presenting molecules. TCRs can bind CD1 proteins with left-sided or right-sided footprints, creating unexpected modes of antigen recognition. The use of tetramers of human CD1a, CD1b, CD1c or MR1 proteins now allows detailed analysis of the human T cell repertoire, which has revealed new invariant TCRs that bind CD1b molecules and are different from those that define natural killer T cells and mucosal-associated invariant T cells.
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References
Garboczi, D. N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).
Garcia, K. C. et al. An αβ T cell receptor structure at 2.5Å and its orientation in the TCR–MHC complex. Science 274, 209–219 (1996).
Zinkernagel, R. M. The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1996. Cellular immune recognition and the biological role of major transplantation antigens. Scand. J. Immunol. 46, 421–436 (1997).
Salerno-Goncalves, R., Fernandez-Vina, M., Lewinsohn, D. M. & Sztein, M. B. Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine. J. Immunol. 173, 5852–5862 (2004).
Heinzel, A. S. et al. HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J. Exp. Med. 196, 1473–1481 (2002).
Adams, E. J. & Luoma, A. M. The adaptable major histocompatibility complex (MHC) fold: structure and function of nonclassical and MHC class I-like molecules. Annu. Rev. Immunol. 31, 529–561 (2013).
de Jong, A. et al. CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire. Nat. Immunol. 11, 1102–1109 (2010).
de Lalla, C. et al. High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells. Eur. J. Immunol. 41, 602–610 (2011).
Kasmar, A. G. et al. CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans. J. Exp. Med. 208, 1741–1747 (2011).
Ly, D. et al. CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J. Exp. Med. 210, 729–741 (2013).
Dellabona, P. et al. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor α/β CD4−8− subset. J. Exp. Med. 177, 1763–1771 (1993).
Gold, M. C. et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 8, e1000407 (2010). Starting with a broad analysis of all human CD8+ T cells, this paper demonstrates an in vivo response of human MAIT cells during natural M. tuberculosis infection.
Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).
Borg, N. A. et al. CD1d–lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448, 44–49 (2007).
Luoma, A. M. et al. Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity 39, 1032–1042 (2013).
Uldrich, A. P. et al. CD1d–lipid antigen recognition by the γδ TCR. Nat. Immunol. 14, 1137–1145 (2013). References 15 and 16 report structures of TRDV1+ γδ TCRs bound to lipid–CD1d complexes, providing detailed molecular mechanisms of CD1 recognition.
Pellicci, D. G. et al. The molecular bases of δ/αβ T cell-mediated antigen recognition. J. Exp. Med. 211, 2599–2615 (2014).
McMichael, A. J. et al. A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody. Eur. J. Immunol. 9, 205–210 (1979).
Calabi, F. & Milstein, C. A novel family of human major histocompatibility complex-related genes not mapping to chromosome 6. Nature 323, 540–543 (1986).
Calabi, F., Jarvis, J. M., Martin, L. & Milstein, C. Two classes of CD1 genes. Eur. J. Immunol. 19, 285–292 (1989).
Dougan, S. K., Kaser, A. & Blumberg, R. S. CD1 expression on antigen-presenting cells. Curr. Top. Microbiol. Immunol. 314, 113–141 (2007).
Porcelli, S. et al. Recognition of cluster of differentiation 1 antigens by human CD4−CD8− cytolytic T lymphocytes. Nature 341, 447–450 (1989). This seminal paper demonstrates that CD1 proteins activate both αβ and γδ T cells. Whereas most work in the field has concentrated on αβ T cells, structural proof of γδ TCR binding to CD1d was finally published in 2013.
Roura-Mir, C. et al. Mycobacterium tuberculosis regulates CD1 antigen presentation pathways through TLR-2. J. Immunol. 175, 1758–1766 (2005).
Baker, M. L. & Miller, R. D. Evolution of mammalian CD1: marsupial CD1 is not orthologous to the eutherian isoforms and is a pseudogene in the opossum Monodelphis domestica. Immunology 121, 113–121 (2007).
Dossa, R. G., Alperin, D. C., Hines, M. T. & Hines, S. A. The equine CD1 gene family is the largest and most diverse yet identified. Immunogenetics 66, 33–42 (2014).
Hayes, S. M. & Knight, K. L. Group 1 CD1 genes in rabbit. J. Immunol. 166, 403–410 (2001).
Van Rhijn, I. et al. The bovine CD1 family contains group 1 CD1 proteins, but no functional CD1d. J. Immunol. 176, 4888–4893 (2006).
Eguchi-Ogawa, T. et al. Analysis of the genomic structure of the porcine CD1 gene cluster. Genomics 89, 248–261 (2007).
Looringh van Beeck, F. A. et al. Two canine CD1a proteins are differentially expressed in skin. Immunogenetics 60, 315–324 (2008).
Kasmar, A., Van Rhijn, I. & Moody, D. B. The evolved functions of CD1 during infection. Curr. Opin. Immunol. 21, 397–403 (2009).
de la Salle, H. et al. Assistance of microbial glycolipid antigen processing by CD1e. Science 310, 1321–1324 (2005).
Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).
Yakimchuk, K. et al. Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-β. Eur. J. Immunol. 41, 694–705 (2011).
Adams, E. J. Lipid presentation by human CD1 molecules and the diverse T cell populations that respond to them. Curr. Opin. Immunol. 26, 1–6 (2014).
Kasmar, A. G. et al. Cutting edge: CD1a tetramers and dextramers identify human lipopeptide-specific T cells ex vivo. J. Immunol. 191, 4499–4503 (2013).
Felio, K. et al. CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic mice. J. Exp. Med. 206, 2497–2509 (2009).
Hiromatsu, K. et al. Induction of CD1-restricted immune responses in guinea pigs by immunization with mycobacterial lipid antigens. J. Immunol. 169, 330–339 (2002).
Dascher, C. C. et al. Conservation of a CD1 multigene family in the guinea pig. J. Immunol. 163, 5478–5488 (1999).
Porcelli, S., Morita, C. T. & Brenner, M. B. CD1b restricts the response of human CD4−8− T lymphoyctes to a microbial antigen. Nature 360, 593–597 (1992).
Beckman, E. M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994).
Layre, E., de Jong, A. & Moody, D. B. Human T cells use CD1 and MR1 to recognize lipids and small molecules. Curr. Opin. Chem. Biol. 23, 31–38 (2014).
Gadola, S. D. et al. Structure of human CD1b with bound ligands at 2.3Å, a maze for alkyl chains. Nat. Immunol. 3, 721–726 (2002). This CD1b structure work provides the earliest structural insights into lipid–CD1 complex formation and initiated functional work on ligand size, accessory portals, spacer lipids and the two-compartment antigen loading model.
Wang, J. et al. Lipid binding orientation within CD1d affects recognition of Borrelia burgorferi antigens by NKT cells. Proc. Natl Acad. Sci. USA 107, 1535–1540 (2010).
Van Rhijn, I. et al. CD1d-restricted T cell activation by nonlipidic small molecules. Proc. Natl Acad. Sci. USA 101, 13578–13583 (2004).
de Jong, A. et al. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat. Immunol. 15, 177–185 (2014). This paper identifies natural, tissue-specific autoantigens for the CD1a system. Surprisingly, these lipid autoantigens were small in size and lacked hydrophilic head groups, which supported a model in which ligands act by absence of interference with the TCR binding.
Prigozy, T. I. et al. Glycolipid antigen processing for presentation by CD1d molecules. Science 291, 664–667 (2001).
Mattner, J. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525–529 (2005).
Cheng, T. Y. et al. Role of lipid trimming and CD1 groove size in cellular antigen presentation. EMBO J. 25, 2989–2999 (2006).
Moody, D. B. et al. Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nat. Immunol. 3, 435–442 (2002).
Huang, S. et al. Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system. Proc. Natl Acad. Sci. USA 108, 19335–19340 (2011).
Garcia-Alles, L. F. et al. Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids. Proc. Natl Acad. Sci. USA 108, 17755–17760 (2011). This paper shows how CD1b ligands of different sizes can slide upwards towards the top of the groove, and it identifies spacer lipids in the CD1b system.
Garcia-Alles, L. F. et al. Endogenous phosphatidylcholine and a long spacer ligand stabilize the lipid-binding groove of CD1b. EMBO J. 25, 3684–3692 (2006).
McCarthy, C. et al. The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation. J. Exp. Med. 204, 1131–1144 (2007).
Jackman, R. M. et al. The tyrosine-containing cytoplasmic tail of CD1b is essential for its efficient presentation of bacterial lipid antigens. Immunity 8, 341–351 (1998).
Relloso, M. et al. pH-dependent interdomain tethers of CD1b regulate its antigen capture. Immunity 28, 774–786 (2008).
Im, J. S. et al. Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30, 888–898 (2009).
Im, J. S. et al. Direct measurement of antigen binding properties of CD1 proteins using fluorescent lipid probes. J. Biol. Chem. 279, 299–310 (2004).
Birkinshaw, R. W. et al. αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nat. Immunol. 16, 258–266 (2015).
Wun, K. S. et al. A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells. Immunity 34, 327–339 (2011).
Zajonc, D. M. et al. Molecular mechanism of lipopeptide presentation by CD1a. Immunity 22, 209–219 (2005).
Scharf, L. et al. The 2.5Å structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity 33, 853–862 (2010). This study analyses a crystal structure of CD1c bound to mannosyl-phosphomycoketide, revealing a large F′ portal, a mechanism for capture of branched chain lipids and two accessory portals.
Zajonc, D. M., Elsliger, M. A., Teyton, L. & Wilson, I. A. Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15Å. Nat. Immunol. 4, 808–815 (2003).
Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).
Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012). This paper provides several advances in the understanding of MAIT cell biology, including the identification of the chemical structures of MR1 antigens as vitamin B metabolites that matched the range of pathogens that activate MAIT cells, as well as the identification of an unexpected mechanism of covalent attachment in generating stable metabolite–MR1 complexes at the surface of cells.
Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).
Eckle, S. B. et al. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. J. Exp. Med. 211, 1585–1600 (2014).
McWilliam, H. E., Birkinshaw, R. W., Villadangos, J. A., McCluskey, J. & Rossjohn, J. MR1 presentation of vitamin B-based metabolite ligands. Curr. Opin. Immunol. 34, 28–34 (2015).
Reantragoon, R. et al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 210, 2305–2320 (2013).
Soudais, C. et al. In vitro and in vivo analysis of the Gram-negative bacteria-derived riboflavin precursor derivatives activating mouse MAIT cells. J. Immunol. 194, 4641–4649 (2015).
Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).
Patel, O. et al. Recognition of vitamin B metabolites by mucosal-associated invariant T cells. Nat. Commun. 4, 2142 (2013).
Tynan, F. E. et al. A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nat. Immunol. 8, 268–276 (2007).
Zeng, Z. et al. Crystal structure of mouse CD1: an MHC-like fold with a large hydrophobic binding groove. Science 277, 339–345 (1997).
Hahn, M., Nicholson, M. J., Pyrdol, J. & Wucherpfennig, K. W. Unconventional topology of self peptide–major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).
Liu, Y. C. et al. A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism. J. Biol. Chem. 289, 16688–16698 (2014).
Brossay, L. et al. Mouse CD1-autoreactive T cells have diverse patterns of reactivity to CD1+ targets. J. Immunol. 160, 3681–3688 (1998).
Mallevaey, T. et al. A molecular basis for NKT cell recognition of CD1d–self-antigen. Immunity 34, 315–326 (2011).
Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).
Rossjohn, J., Pellicci, D. G., Patel, O., Gapin, L. & Godfrey, D. I. Recognition of CD1d-restricted antigens by natural killer T cells. Nat. Rev. Immunol. 12, 845–857 (2012).
Roy, S. et al. Molecular basis of mycobacterial lipid antigen presentation by CD1c and its recognition by αβ T cells. Proc. Natl Acad. Sci. USA 111, E4648–E4657 (2014).
Garboczi, D. N. et al. Assembly, specific binding, and crystallization of a human TCR-αβ with an antigenic Tax peptide from human T lymphotropic virus type 1 and the class I MHC molecule HLA-A2. J. Immunol. 157, 5403–5410 (1996).
Moody, D. B. et al. Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278, 283–286 (1997).
Manolova, V. et al. Functional CD1a is stabilized by exogenous lipids. Eur. J. Immunol. 36, 1083–1092 (2006).
Sugita, M. et al. Separate pathways for antigen presentation by CD1 molecules. Immunity 11, 743–752 (1999).
Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
Moody, D. B. et al. T cell activation by lipopeptide antigens. Science 303, 527–531 (2004).
Young, D. C. et al. Synthesis of dideoxymycobactin antigens presented by CD1a reveals T cell fine specificity for natural lipopeptide structures. J. Biol. Chem. 284, 25087–25096 (2009).
Shamshiev, A. et al. Presentation of the same glycolipid by different CD1 molecules. J. Exp. Med. 195, 1013–1021 (2002).
Agea, E. et al. Human CD1-restricted T cell recognition of lipids from pollens. J. Exp. Med. 202, 295–308 (2005).
Bourgeois, E. A. et al. Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med. 212, 149–163 (2015).
Chien, Y. H., Meyer, C. & Bonneville, M. γδ T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121–155 (2014).
Tanaka, Y., Morita, C. T., Nieves, E., Brenner, M. B. & Bloom, B. R. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995).
Bukowski, J. F., Morita, C. T. & Brenner, M. B. Human γδ T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity. Immunity 11, 57–65 (1999).
Tanaka, Y. et al. Nonpeptide ligands for human γδ T cells. Proc. Natl Acad. Sci. USA 91, 8175–8179 (1994).
Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14, 908–916 (2013).
Adams, E. J., Gu, S. & Luoma, A. M. Human γδ T cells: evolution and ligand recognition. Cell. Immunol. 296, 31–40 (2015).
Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40, 490–500 (2014).
Willcox, C. R. et al. Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nat. Immunol. 13, 872–879 (2012).
Leslie, D. S. et al. CD1-mediated γ/δ T cell maturation of dendritic cells. J. Exp. Med. 196, 1575–1584 (2002).
Spada, F. M., Koezuka, Y. & Porcelli, S. A. CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells. J. Exp. Med. 188, 1529–1534 (1998).
Bai, L. et al. The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vδ1 TCR. Eur. J. Immunol. 42, 2505–2510 (2012).
Lefranc, M. P. & Rabbitts, T. H. Genetic organization of the human T-cell receptor gamma and delta loci. Res. Immunol. 141, 565–577 (1990).
Miossec, C. et al. Further analysis of the T cell receptor γ/δ+ peripheral lymphocyte subset. The Vδ1 gene segment is expressed with either Cα or Cδ. J. Exp. Med. 171, 1171–1188 (1990).
Miossec, C. et al. Molecular characterization of human T cell receptor α chains including a Vδ1-encoded variable segment. Eur. J. Immunol. 21, 1061–1064 (1991).
Peyrat, M. A. et al. Repertoire analysis of human peripheral blood lymphocytes using a human Vδ3 region-specific monoclonal antibody. Characterization of dual T cell receptor (TCR) δ-chain expressors and αβ T cells expressing Vδ3JαCα-encoded TCR chains. J. Immunol. 155, 3060–3067 (1995).
Dieude, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted γδ T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).
Mangan, B. A. et al. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human vδ3 T cells. J. Immunol. 191, 30–34 (2013).
Fowlkes, B. J. et al. A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ gene family. Nature 329, 251–254 (1987).
Budd, R. C. et al. Developmentally regulated expression of T cell receptor β chain variable domains in immature thymocytes. J. Exp. Med. 166, 577–582 (1987).
Tilloy, F. et al. An invariant T cell receptor α chain defines a novel TAP- independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999).
Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).
Van Rhijn, I. et al. TCR bias and affinity define two compartments of the CD1b–glycolipid-specific T cell repertoire. J. Immunol. 192, 4054–4060 (2014).
Van Rhijn, I. et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat. Immunol. 14, 706–713 (2013). Expanding the field of invariant T cells beyond NKT cells and MAIT cells, this paper discovered human GEM T cells specific for CD1b.
Grant, E. P. et al. Molecular recognition of lipid antigens by T cell receptors. J. Exp. Med. 189, 195–205 (1999).
Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).
van Schaik, B. et al. Discovery of invariant T cells by next-generation sequencing of the human TCR α-chain repertoire. J. Immunol. 193, 5338–5344 (2014).
Le Bourhis, L., Mburu, Y. K. & Lantz, O. MAIT cells, surveyors of a new class of antigen: development and functions. Curr. Opin. Immunol. 25, 174–180 (2013).
Fernandez, C. S. et al. MAIT cells are depleted early but retain functional cytokine expression in HIV infection. Immunol. Cell Biol. 93, 177–188 (2015).
Gold, M. C. et al. Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. Mucosal Immunol. 6, 35–44 (2013).
Miyamoto, K., Miyake, S. & Yamamura, T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413, 531–534 (2001).
Kim, E. Y., Lynch, L., Brennan, P. J., Cohen, N. R. & Brenner, M. B. The transcriptional programs of iNKT cells. Semin. Immunol. 27, 26–32 (2015).
Fujii, S. et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front. Immunol. 4, 409 (2013).
Tefit, J. N. et al. Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination. Vaccine 32, 6138–6145 (2014).
Motohashi, S. et al. A Phase I–II study of α-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J. Immunol. 182, 2492–2501 (2009).
Schneiders, F. L. et al. Clinical experience with α-galactosylceramide (KRN7000) in patients with advanced cancer and chronic hepatitis B/C infection. Clin. Immunol. 140, 130–141 (2011).
Salomonsen, J. et al. Two CD1 genes map to the chicken MHC, indicating that CD1 genes are ancient and likely to have been present in the primordial MHC. Proc. Natl Acad. Sci. USA 102, 8668–8673 (2005).
Miller, M. M. et al. Characterization of two avian MHC-like genes reveals an ancient origin of the CD1 family. Proc. Natl Acad. Sci. USA 102, 8674–8679 (2005).
Nguyen, T. K. A. et al. Expression patterns of bovine CD1 in vivo and assessment of the specificities of the anti-bovine CD1 antibodies. PLoS ONE 10, e129755 (2015).
Looringh van Beeck, F. A. et al. Functional CD1d and/or NKT cell invariant chain transcript in horse, pig, African elephant and guinea pig, but not in ruminants. Mol. Immunol. 46, 1424–1431 (2009).
Acknowledgements
The authors thank R. Birkinshaw, J. Le Nours, S. Huang, T.-Y. Cheng and K. Wucherpfennig for advice and graphical images. This work is supported by the Bill and Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases (NIAID; grants AI049313, AI111224 and U19 111224), National Health and Medical Research Council (NHMRC) of Australia (1013667 and 1083942), Australian Research Council (DP140100977 and CE140100011), Cancer Council of Victoria (1042866), NHMRC Senior Principal Research Fellowship (to D.I.G.; 1020770) and NHMRC Australia Fellowship (to J.R.; AF50). All figures, including figure 1 and figure 5b, are original.
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Glossary
- Accessory portals
-
Small gaps present in the side or bottom of the clefts present in CD1b (C′ portal) and CD1c (D′ and E′ portals). Whereas the main F′ portal is present in all CD1 proteins and allows antigen contact with T cell receptors (TCRs), accessory portals probably have a separate sizing function that allows lipids to partially escape from the interior of the cleft at a site distant from TCR contact.
- Tetramers
-
Reagents comprised of a fluorophore-conjugated core surrounded by four antigen-presenting molecules (for example, MHC class l, CD1 or MR1). Antigen-loaded tetramers bind antigen-specific T cell receptors with sufficient avidity so that antigen-specific T cells can be directly counted or isolated by flow cytometry.
- Wax esters
-
Fatty acids linked to an alcohol to form hydrophobic lipids, including those that accumulate on the skin surface.
- Squalene
-
An abundant, organ-specific polyunsaturated branched chain lipid with 30 carbons that accumulates in the skin and activates T cells via CD1a.
- Scaffold lipids
-
Specialized types of spacer lipid that are located within the lower section (T′ tunnel) of the CD1b cleft. Scaffold is an analogy to building scaffolds, which provide upwards-directed support to larger objects, which in this case is the antigen.
- Class II-associated invariant chain peptide
-
(CLIP). A short amino acid sequence in the invariant chain that binds within the MHC class II groove shortly after translation so that it functions to block loading of self peptides during the early stages of MHC class II exit from the endoplasmic reticulum and Golgi apparatus.
- Secretory pathway
-
A series of protein transport reactions in which newly folded proteins transit from the endoplasmic reticulum to the Golgi apparatus and to the cell surface. For CD1, this pathway provides self lipids that are loaded onto CD1 proteins at neutral pH.
- Endosomal recycling
-
A process by which CD1 proteins shuttle from the cell surface to the endosomal network and back. CD1b, CD1c and CD1d proteins contain tyrosine-containing motifs in their cytoplasmic tails that mediate binding to adaptor proteins and transport to endosomes and lysosomes, where lipids derived from outside the antigen-presenting cell bind CD1 proteins at neutral or acidic pH.
- Spacer lipids
-
Hydrophobic compounds that bind alongside antigenic lipids and fill up part of the CD1 cleft that is not occupied.
- Mucosal-associated invariant T cells
-
(MAIT cells). T cells that express a structurally conserved invariant T cell receptor and are selected by MR1.
- Sebum
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Mixed hydrophobic oils that are produced by glands in the hair follicles and released to form an outer protective barrier on the skin surface.
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Van Rhijn, I., Godfrey, D., Rossjohn, J. et al. Lipid and small-molecule display by CD1 and MR1. Nat Rev Immunol 15, 643–654 (2015). https://doi.org/10.1038/nri3889
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DOI: https://doi.org/10.1038/nri3889