The burgeoning family of unconventional T cells

Article metrics

  • A Corrigendum to this article was published on 19 January 2016
  • A Corrigendum to this article was published on 22 March 2016


While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib–reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Comparison of unconventional and MHC-restricted T cell responses.
Figure 2: Unconventional αβ T cell populations.
Figure 3: Populations of γδ T cells.
Figure 4: Frequency of some antigen-specific T cell types.
Figure 5: Antigens detected by unconventional αβ T cells.

Change history

  • 13 November 2015

    In the version of this article initially published, the vertical axes of Figure 4 were labeled incorrectly as "(per 1 × 105 T cells)." The correct label is "(per 1 × 106 T cells)." These errors have been corrected for the PDF and HTML versions of this article.


  1. 1

    Lieber, M.R. Site-specific recombination in the immune system. FASEB J. 5, 2934–2944 (1991).

  2. 2

    Arstila, T.P. et al. A direct estimate of the human alphabeta T cell receptor diversity. Science 286, 958–961 (1999).

  3. 3

    Jenkins, M.K. & Moon, J.J. The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J. Immunol. 188, 4135–4140 (2012).

  4. 4

    Calabi, F., Jarvis, J.M., Martin, L. & Milstein, C. Two classes of CD1 genes. Eur. J. Immunol. 19, 285–292 (1989).

  5. 5

    Kasmar, A., Van Rhijn, I. & Moody, D.B. The evolved functions of CD1 during infection. Curr. Opin. Immunol. 21, 397–403 (2009).

  6. 6

    Dougan, S.K., Kaser, A. & Blumberg, R.S. CD1 expression on antigen-presenting cells. Curr. Top. Microbiol. Immunol. 314, 113–141 (2007).

  7. 7

    Van Rhijn, I., Godfrey, D., Rossjohn, J. & Moody, D.B. Lipid and small-molecule display by CD1 and MR1. Nat. Rev. Immunol. 15, 643–654 (2015).

  8. 8

    Godfrey, D.I., MacDonald, H.R., Kronenberg, M., Smyth, M.J. & Van Kaer, L. NKT cells: what's in a name? Nat. Rev. Immunol. 4, 231–237 (2004).

  9. 9

    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).

  10. 10

    Rhost, S., Sedimbi, S., Kadri, N. & Cardell, S.L. Immunomodulatory type II natural killer T lymphocytes in health and disease. Scand. J. Immunol. 76, 246–255 (2012).

  11. 11

    Kawano, T. et al. Cd1d-restricted and TCR-mediated Activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

  12. 12

    Cerundolo, V., Silk, J.D., Masri, S.H. & Salio, M. Harnessing invariant NKT cells in vaccination strategies. Nat. Rev. Immunol. 9, 28–38 (2009).

  13. 13

    Fujii, S.I. et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front. Immunology 4, 409 (2013).

  14. 14

    Hammond, K.J.L. et al. CD1d-restricted NKT cells: An interstrain comparison. J. Immunol. 167, 1164–1173 (2001).

  15. 15

    Chan, A.C. et al. Ex-vivo analysis of human natural killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4 subsets. Clin. Exp. Immunol. 172, 129–137 (2013).

  16. 16

    Pei, B., Vela, J.L., Zajonc, D. & Kronenberg, M. Interplay between carbohydrate and lipid in recognition of glycolipid antigens by natural killer T cells. Ann. NY Acad. Sci. 1253, 68–79 (2012).

  17. 17

    Speak, A.O. et al. Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals. Proc. Natl. Acad. Sci. USA 104, 5971–5976 (2007).

  18. 18

    Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

  19. 19

    Brennan, P.J. et al. Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction. Proc. Natl. Acad. Sci. USA 111, 13433–13438 (2014).

  20. 20

    Kain, L. et al. The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian alpha-linked glycosylceramides. Immunity 41, 543–554 (2014).

  21. 21

    Kain, L. et al. Endogenous ligands of natural killer T cells are α-linked glycosylceramides. Mol. Immunol. doi:10.1016/j.molimm.2015.06.009 (30 June 2015).

  22. 22

    Wieland Brown, L.C. et al. Production of α-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol. 11, e1001610 (2013).

  23. 23

    Crowe, N.Y. et al. Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells. J. Immunol. 171, 4020–4027 (2003).

  24. 24

    Wilson, M.T. et al. The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion. Proc. Natl. Acad. Sci. USA 100, 10913–10918 (2003).

  25. 25

    Coquet, J.M. et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4NK1.1 NKT cell population. Proc. Natl. Acad. Sci. USA 105, 11287–11292 (2008).

  26. 26

    Wingender, G., Krebs, P., Beutler, B. & Kronenberg, M. Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency. J. Immunol. 185, 2721–2729 (2010).

  27. 27

    Vincent, M.S. et al. CD1-dependent dendritic cell instruction. Nat. Immunol. 3, 1163–1168 (2002).

  28. 28

    Fujii, S., Liu, K., Smith, C., Bonito, A.J. & Steinman, R.M. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J. Exp. Med. 199, 1607–1618 (2004).

  29. 29

    Eberl, G. & MacDonald, H.R. Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells. Eur. J. Immunol. 30, 985–992 (2000).

  30. 30

    Galli, G. et al. CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J. Exp. Med. 197, 1051–1057 (2003).

  31. 31

    Salio, M., Silk, J.D., Yvonne Jones, E. & Cerundolo, V. Biology of CD1- and MR1-restricted T cells. Annu. Rev. Immunol. 32, 323–366 (2014).

  32. 32

    Wu, L. & Van Kaer, L. Natural killer T cells in health and disease. Front. Biosci. 3, 236–251 (2011).

  33. 33

    De Santo, C. et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J. Clin. Invest. 118, 4036–4048 (2008).

  34. 34

    Guillonneau, C. et al. Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity. Proc. Natl. Acad. Sci. USA 106, 3330–3335 (2009).

  35. 35

    Chang, P.P. et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat. Immunol. 13, 35–43 (2011).

  36. 36

    Lee, 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. 14, 1146–1154 (2013).

  37. 37

    Michel, M.L. et al. Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia. J. Exp. Med. 204, 995–1001 (2007).

  38. 38

    Sag, D., Krause, P., Hedrick, C.C., Kronenberg, M. & Wingender, G. IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset. J. Clin. Invest. 124, 3725–3740 (2014).

  39. 39

    King, I.L. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat. Immunol. 13, 44–50 (2012).

  40. 40

    Yamasaki, K. et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin. Immunol. 138, 255–265 (2011).

  41. 41

    Schmieg, J., Yang, G., Franck, R.W. & Tsuji, M. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand α-galactosylceramide. J. Exp. Med. 198, 1631–1641 (2003).

  42. 42

    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).

  43. 43

    Bedel, R. et al. Lower TCR repertoire diversity in Traj18-deficient mice. Nat. Immunol. 13, 705–706 (2012).

  44. 44

    Chandra, S. et al. A new mouse strain for the analysis of invariant NKT cell function. Nat. Immunol. 16, 799–800 (2015).

  45. 45

    Jahng, A. et al. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J. Exp. Med. 199, 947–957 (2004).

  46. 46

    Terabe, M. et al. A nonclassical non-Vα14Jα18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J. Exp. Med. 202, 1627–1633 (2005).

  47. 47

    Ambrosino, E. et al. Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis. J. Immunol. 179, 5126–5136 (2007).

  48. 48

    Robertson, F.C., Berzofsky, J.A. & Terabe, M. NKT cell networks in the regulation of tumor immunity. Front. Immunology 5, 543 (2014).

  49. 49

    Chang, D.H. et al. Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer. Blood 112, 1308–1316 (2008).

  50. 50

    Tatituri, R.V. et al. Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc. Natl. Acad. Sci. USA 110, 1827–1832 (2013).

  51. 51

    Zeissig, S. et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat. Med. 18, 1060–1068 (2012).

  52. 52

    Van Rhijn, I. et al. CD1d-restricted T cell activation by nonlipidic small molecules. Proc. Natl. Acad. Sci. USA 101, 13578–13583 (2004).

  53. 53

    Exley, M.A. et al. Cutting edge: A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J. Immunol. 167, 5531–5534 (2001).

  54. 54

    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).

  55. 55

    Beckman, E.M. et al. Recognition of a lipid antigen by CD1-restricted ab+ T cells. Nature 372, 691–694 (1994).

  56. 56

    Van Rhijn, I. & Moody, D. Donor unrestricted T cells: a shared human T cell response. J. Immunol. 195, 1927–1932 (2015).

  57. 57

    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).

  58. 58

    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).

  59. 59

    Ly, D. et al. CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J. Exp. Med. 210, 729–741 (2013).

  60. 60

    Van Rhijn, I. et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat. Immunol. 14, 706–713 (2013).

  61. 61

    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).

  62. 62

    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).

  63. 63

    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).

  64. 64

    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).

  65. 65

    de Jong, A. et al. CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat. Immunol. 15, 177–185 (2014).

  66. 66

    Bourgeois, E.A. et al. Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med. 212, 149–163 (2015).

  67. 67

    Porcelli, S. et al. Recognition of cluster of differentiation 1 antigens by human CD4CD8 cytolytic T lymphocytes. Nature 341, 447–450 (1989).

  68. 68

    Lepore, M. et al. A novel self-lipid antigen targets human T cells against CD1c+ leukemias. J. Exp. Med. 211, 1363–1377 (2014).

  69. 69

    Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).

  70. 70

    Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

  71. 71

    Ussher, J.E., Klenerman, P. & Willberg, C.B. Mucosal-associated invariant T-cells: new players in anti-bacterial immunity. Front. Immunol. 5, 450 (2014).

  72. 72

    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).

  73. 73

    Gold, M.C. et al. MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J. Exp. Med. 211, 1601–1610 (2014).

  74. 74

    Lepore, M. et al. Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire. Nat. Commun. 5, 3866 (2014).

  75. 75

    Rahimpour, A. et al. Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J. Exp. Med. 212, 1095–1108 (2015).

  76. 76

    Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).

  77. 77

    Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).

  78. 78

    Gold, M.C. et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 8, e1000407 (2010).

  79. 79

    Corbett, A.J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).

  80. 80

    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).

  81. 81

    Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

  82. 82

    Patel, O. et al. Recognition of vitamin B metabolites by mucosal-associated invariant T cells. Nat. Commun. 4, 2142 (2013).

  83. 83

    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).

  84. 84

    Meierovics, A., Yankelevich, W.J. & Cowley, S.C. MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection. Proc. Natl. Acad. Sci. USA 110, E3119–E3128 (2013).

  85. 85

    Leeansyah, E. et al. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood 121, 1124–1135 (2013).

  86. 86

    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).

  87. 87

    Leeansyah, E. et al. Arming of MAIT cell cytolytic antimicrobial activity is induced by IL-7 and defective in HIV-1 infection. PLoS Pathog. 11, e1005072 (2015).

  88. 88

    Ussher, J.E. et al. CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur. J. Immunol. 44, 195–203 (2014).

  89. 89

    Croxford, J.L., Miyake, S., Huang, Y.Y., Shimamura, M. & Yamamura, T. Invariant Vα19i T cells regulate autoimmune inflammation. Nat. Immunol. 7, 987–994 (2006).

  90. 90

    Serriari, N.E. et al. Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin. Exp. Immunol. 176, 266–274 (2014).

  91. 91

    Magalhaes, I. et al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125, 1752–1762 (2015).

  92. 92

    Teunissen, M.B. et al. The IL-17A-producing CD8 T cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J. Invest. Dermatol. 134, 2898–2907 (2014).

  93. 93

    Cho, Y.N. et al. Mucosal-associated invariant T cell deficiency in systemic lupus erythematosus. J. Immunol. 193, 3891–3901 (2014).

  94. 94

    Smith, D.J., Hill, G.R., Bell, S.C. & Reid, D.W. Reduced mucosal associated invariant T-cells are associated with increased disease severity and Pseudomonas aeruginosa infection in cystic fibrosis. PLoS ONE 9, e109891 (2014).

  95. 95

    Chien, Y.H., Meyer, C. & Bonneville, M. gammadelta T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121–155 (2014).

  96. 96

    Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

  97. 97

    Rock, E.P., Sibbald, P.R., Davis, M.M. & Chien, Y.H. CDR3 length in antigen-specific immune receptors. J. Exp. Med. 179, 323–328 (1994).

  98. 98

    O'Brien, R.L. & Born, W.K. Dermal γδ T cells—What have we learned? Cell. Immunol. 296, 62–69 (2015).

  99. 99

    Takagaki, Y., DeCloux, A., Bonneville, M. & Tonegawa, S. Diversity of γδ T-cell receptors on murine intestinal intra-epithelial lymphocytes. Nature 339, 712–714 (1989).

  100. 100

    Pereira, P., Lafaille, J.J., Gerber, D. & Tonegawa, S. The T cell receptor repertoire of intestinal intraepithelial γδ T lymphocytes is influenced by genes linked to the major histocompatibility complex and to the T cell receptor loci. Proc. Natl. Acad. Sci. USA 94, 5761–5766 (1997).

  101. 101

    Gerber, D.J. et al. IL4-producing γδ T cells that express a very restricted TCR repertoire are preferentially localized in liver and spleen. J. Immunol. 163, 3076–3082 (1999).

  102. 102

    Sim, G.K., Rajaserkar, R., Dessing, M. & Augustin, A. Homing and in situ differentiation of resident pulmonary lymphocytes. Int. Immunol. 6, 1287–1295 (1994).

  103. 103

    Itohara, S. et al. Homing of a γδ thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).

  104. 104

    O'Brien, R.L. & Born, W.K. γδ T cell subsets: a link between TCR and function? Semin. Immunol. 22, 193–198 (2010).

  105. 105

    Ebert, L.M., Meuter, S. & Moser, B. Homing and function of human skin T cells and NK cells: relevance for tumor surveillance. J. Immunol. 176, 4331–4336 (2006).

  106. 106

    Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

  107. 107

    Deusch, K. et al. A major fraction of human intraepithelial lymphocytes simultaneously expresses the γδ T cell receptor, the CD8 accessory molecule and preferentially uses the Vδ1 gene segment. Eur. J. Immunol. 21, 1053–1059 (1991).

  108. 108

    Karunakaran, M.M., Gobel, T.W., Starick, L., Walter, L. & Herrmann, T. Vγ9 and Vδ2 T cell antigen receptor genes and butyrophilin 3 (BTN3) emerged with placental mammals and are concomitantly preserved in selected species like alpaca (Vicugna pacos). Immunogenetics 66, 243–254 (2014).

  109. 109

    Hintz, M. et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human γδ T cells in Escherichia coli. FEBS Lett. 509, 317–322 (2001).

  110. 110

    Gu, S., Nawrocka, W. & Adams, E.J. Sensing of pyrophosphate metabolites by Vγ9Vδ2 T cells. Front. Immunol. 5, 688 (2014).

  111. 111

    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).

  112. 112

    Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995).

  113. 113

    Li, H. et al. Structure of the Vδ domain of a human γδ T-cell antigen receptor. Nature 391, 502–506 (1998).

  114. 114

    Allison, T.J., Winter, C.C., Fournie, J.J., Bonneville, M. & Garboczi, D.N. Structure of a human γδ T-cell antigen receptor. Nature 411, 820–824 (2001).

  115. 115

    Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14, 908–916 (2013).

  116. 116

    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).

  117. 117

    Rhodes, D.A. et al. Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin. J. Immunol. 194, 2390–2398 (2015).

  118. 118

    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).

  119. 119

    Spada, F.M. et al. Self-recognition of CD1 by γδ T cells: implications for innate immunity. J. Exp. Med. 191, 937–948 (2000).

  120. 120

    Uldrich, A.P. et al. CD1d-lipid antigen recognition by the γδ TCR. Nat. Immunol. 14, 1137–1145 (2013).

  121. 121

    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).

  122. 122

    Wu, J., Groh, V. & Spies, T. T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial γδ T cells. J. Immunol. 169, 1236–1240 (2002).

  123. 123

    Kong, Y. et al. The NKG2D ligand ULBP4 binds to TCRγ9/δ2 and induces cytotoxicity to tumor cells through both TCRγδ and NKG2D. Blood 114, 310–317 (2009).

  124. 124

    Luoma, A.M. et al. Crystal structure of Vdelta1 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).

  125. 125

    Agea, E. et al. Human CD1-restricted T cell recognition of lipids from pollens. J. Exp. Med. 202, 295–308 (2005).

  126. 126

    Russano, A.M. et al. Recognition of pollen-derived phosphatidyl-ethanolamine by human CD1d-restricted γδ T cells. J. Allergy Clin. Immunol. 117, 1178–1184 (2006).

  127. 127

    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).

  128. 128

    Zeng, X. et al. γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity 37, 524–534 (2012).

  129. 129

    Bruder, J. et al. Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. J. Biol. Chem. 287, 20986–20995 (2012).

  130. 130

    Rodgers, J.R. & Cook, R.G. MHC class Ib molecules bridge innate and acquired immunity. Nat. Rev. Immunol. 5, 459–471 (2005).

  131. 131

    Sullivan, L.C., Clements, C.S., Rossjohn, J. & Brooks, A.G. The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity. Tissue Antigens 72, 415–424 (2008).

  132. 132

    Barakonyi, A. et al. Recognition of nonclassical HLA class I antigens by γδ T cells during pregnancy. J. Immunol. 168, 2683–2688 (2002).

  133. 133

    Cho, H., Choi, H.-J., Xu, H., Felio, K. & Wang, C.-R. Nonconventional CD8+ T cell responses to listeria infection in mice lacking MHC class Ia and H2–M3. J. Immunol. 186, 489–498 (2011).

  134. 134

    Caccamo, N. et al. Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA-E during active tuberculosis and express type 2 cytokines. Eur. J. Immunol. 45, 1069–1081 (2015).

  135. 135

    van Meijgaarden, K.E. et al. Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. PLoS Pathog. 11, e1004671 (2015).

  136. 136

    Sullivan, L.C., Hoare, H.L., McCluskey, J., Rossjohn, J. & Brooks, A.G. A structural perspective on MHC class Ib molecules in adaptive immunity. Trends Immunol. 27, 413–420 (2006).

  137. 137

    Chiu, N.M. et al. The selection of M3-restricted T cells is dependent on M3 expression and presentation of N-formylated peptides in the thymus. J. Exp. Med. 190, 1869–1878 (1999).

  138. 138

    Swanson, P.A. et al. An MHC class Ib–restricted CD8 T cell response confers antiviral immunity. J. Exp. Med. 205, 1647–1657 (2008).

  139. 139

    Chiang, E.Y. & Stroynowski, I. Protective immunity against disparate tumors is mediated by a nonpolymorphic MHC class I molecule. J. Immunol. 174, 5367–5374 (2005).

  140. 140

    Hofstetter, A.R. et al. MHC class Ib-restricted CD8 T cells differ in dependence on CD4 T cell Help and CD28 costimulation over the course of mouse polyomavirus infection. J. Immunol. 188, 3071–3079 (2012).

  141. 141

    Rohrlich, P.S. et al. Direct recognition by αβ cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Natl. Acad. Sci. USA 102, 12855–12860 (2005).

  142. 142

    Crowley, M.P. et al. A population of murine γδ T cells that recognize an inducible MHC class Ib molecule. Science 287, 314–316 (2000).

  143. 143

    Crowley, M.P., Reich, Z., Mavaddat, N., Altman, J.D. & Chien, Y. The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the γδ T cell, G8. J. Exp. Med. 185, 1223–1230 (1997).

  144. 144

    Tefit, J.N. et al. Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination. Vaccine 32, 6138–6145 (2014).

  145. 145

    Gomes, A.Q., Martins, D.S. & Silva-Santos, B. Targeting γδ T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application. Cancer Res. 70, 10024–10027 (2010).

  146. 146

    Birkinshaw, R.W. et al. αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nat. Immunol. 16, 258–266 (2015).

  147. 147

    Tefit, J.N., Davies, G. & Serra, V. NKT cell responses to glycolipid activation. Methods Mol. Biol. 626, 149–167 (2010).

  148. 148

    Shimizu, K., Kurosawa, Y., Taniguchi, M., Steinman, R.M. & Fujii, S. Cross-presentation of glycolipid from tumor cells loaded with α-galactosylceramide leads to potent and long-lived T cell mediated immunity via dendritic cells. J. Exp. Med. 204, 2641–2653 (2007).

  149. 149

    Venkataswamy, M.M. et al. Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium bovis bacillus Calmette-Guerin. J. Immunol. 183, 1644–1656 (2009).

  150. 150

    Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 15, 457–472 (2015).

  151. 151

    Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

  152. 152

    Dupuy, P. et al. T-cell receptor-γδ bearing lymphocytes in normal and inflammatory human skin. J. Invest. Dermatol. 94, 764–768 (1990).

  153. 153

    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).

  154. 154

    Lockridge, J.L. et al. Analysis of the CD1 antigen presenting system in humanized SCID mice. PLoS ONE 6, e21701 (2011).

  155. 155

    Dascher, C.C. et al. Conservation of a CD1 multigene family in the guinea pig. J. Immunol. 163, 5478–5488 (1999).

  156. 156

    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).

  157. 157

    Ly, D. et al. CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J. Exp. Med. 210, 729–741 (2013).

  158. 158

    Berzins, S.P., Cochrane, A.D., Pellicci, D.G., Smyth, M.J. & Godfrey, D.I. Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples. Eur. J. Immunol. 35, 1399–1407 (2005).

  159. 159

    Matsuda, J.L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

Download references


We thank M. Sugita and N. LaGruta for discussions. Supported by the National Health and Medical Research Council of Australia (1013667 and 1063587; 1020770 to D.I.G.; and AF50 to J.R.), the Australian Research Council (CE140100011 and LE110100106; and FT140100278 to A.P.U.), Cancer Council Victoria, the Bill and Melinda Gates Foundation Vaccine Accelerator, and the National Institute of Allergy and Infectious Diseases (AI049313, AR048632 and U19111224).

Author information

Correspondence to Dale I Godfrey.

Ethics declarations

Competing interests

D.I.G. is chair of the scientific advisory panel for Avalia Immunotherapies.

Supplementary information

Supplementary Table 1

Characteristics of non-conventional T cells (PDF 43 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Godfrey, D., Uldrich, A., McCluskey, J. et al. The burgeoning family of unconventional T cells. Nat Immunol 16, 1114–1123 (2015) doi:10.1038/ni.3298

Download citation

Further reading