Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A multilayered immune system through the lens of unconventional T cells

Abstract

The unconventional T cell compartment encompasses a variety of cell subsets that straddle the line between innate and adaptive immunity, often reside at mucosal surfaces and can recognize a wide range of non-polymorphic ligands. Recent advances have highlighted the role of unconventional T cells in tissue homeostasis and disease. In this Review, we recast unconventional T cell subsets according to the class of ligand that they recognize; their expression of semi-invariant or diverse T cell receptors; the structural features that underlie ligand recognition; their acquisition of effector functions in the thymus or periphery; and their distinct functional properties. Unconventional T cells follow specific selection rules and are poised to recognize self or evolutionarily conserved microbial antigens. We discuss these features from an evolutionary perspective to provide insights into the development and function of unconventional T cells. Finally, we elaborate on the functional redundancy of unconventional T cells and their relationship to subsets of innate and adaptive lymphoid cells, and propose that the unconventional T cell compartment has a critical role in our survival by expanding and complementing the role of the conventional T cell compartment in protective immunity, tissue healing and barrier function.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Comparison of TCR docking modes.
Fig. 2: Classification of non-classical T cells on the basis of central or peripheral development.
Fig. 3: Functional niche of unconventional T cells.
Fig. 4: Conservation and redundancy within the T cell compartment.

References

  1. 1.

    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).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Lu, L., Werneck, M. B. F. & Cantor, H. The immunoregulatory effects of Qa-1. Immunol. Rev. 212, 51–59 (2006).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Colmone, A. & Wang, C.-R. H2-M3-restricted T cell response to infection. Microbes Infect. 8, 2277–2283 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    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).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Kim, H.-J. & Cantor, H. Regulation of self-tolerance by Qa-1-restricted CD8+ regulatory T cells. Semin. Immunol. 23, 446–452 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Godfrey, D. I., Uldrich, A. P., McCluskey, J., Rossjohn, J. & Moody, D. B. The burgeoning family of unconventional T cells. Nat. Immunol. 16, 1114–1123 (2015).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Mayassi, T. & Jabri, B. Human intraepithelial lymphocytes. Mucosal Immunol. 11, 1281–1289 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Ogg, G., Cerundolo, V. & McMichael, A. J. Capturing the antigen landscape: HLA-E, CD1 and MR1. Curr. Opin. Immunol. 59, 121–129 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Legoux, F., Salou, M. & Lantz, O. MAIT cell development and functions: the microbial connection. Immunity 53, 710–723 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Nielsen, M. M., Witherden, D. A. & Havran, W. L. γδ T cells in homeostasis and host defence of epithelial barrier tissues. Nat. Rev. Immunol. 17, 733–745 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Jouand, N. et al. HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition. PLoS Pathog. 14, e1007041 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Bian, Y. et al. MHC Ib molecule Qa-1 presents Mycobacterium tuberculosis peptide antigens to CD8+ T cells and contributes to protection against infection. PLoS Pathog. 13, e1006384 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995). This paper demonstrates that NKT cells recognize CD1d.

    ADS  CAS  PubMed  Article  Google Scholar 

  17. 17.

    Mattner, J. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525–529 (2005). This paper and the following reference show that NKT cells promote defence against bacterial infections by recognizing either self or microbial glycolipids.

    ADS  CAS  PubMed  Article  Google Scholar 

  18. 18.

    Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005).

    ADS  CAS  PubMed  Article  Google Scholar 

  19. 19.

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

    ADS  CAS  PubMed  Article  Google Scholar 

  20. 20.

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

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Shawar, S. M., Rodgers, J. R., Cook, R. G. & Rich, R. R. Specialized function of the nonclassical MHC class I molecule Hmt: a specific receptor for N-formylated peptides. Immunol. Res. 10, 365–375 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Lenz, L. L., Dere, B. & Bevan, M. J. Identification of an H2-M3-restricted Listeria epitope: implications for antigen presentation by M3. Immunity 5, 63–72 (1996). This paper shows that the non-classical MHC molecule H2-M3 presents bacterial formylated peptides.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

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

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  25. 25.

    Birkinshaw, R. W. et al. αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nat. Immunol. 16, 258–266 (2015). The crystal structures in this paper show the breaking of the co-recognition paradigm as defined by the requirement for a TCR to simultaneously recognize an antigen and the antigen-presenting molecule.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Dimova, T. et al. Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire. Proc. Natl Acad. Sci. USA 112, E556–E565 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Jabri, B. et al. TCR specificity dictates CD94/NKG2A expression by human CTL. Immunity 17, 487–499 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Oliveira, C. C. et al. The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects. J. Exp. Med. 207, 207–221 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Barbee, S. D. et al. Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl Acad. Sci. USA 108, 3330–3335 (2011). This paper identifies SKINT-1 as the selecting ligand for DETCs.

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Di Marco Barros, R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific γδ t cell compartments. Cell 167, 203–218 (2016). This paper identifies BTNL molecules as the selecting ligands for gut-specific γδ T cells.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Mayassi, T. et al. Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease. Cell 176, 967–981 (2019). This paper characterizes the functional and transcriptional program of the gut innate-like human BTNL-specific γδ T cells and shows how chronic inflammation permanently reshapes these niches.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Shin, S. et al. Antigen recognition determinants of γδ T cell receptors. Science 308, 252–255 (2005).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Lantz, O. & Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD48 T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Kawano, T. et al. CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD48 α/β T cells demonstrates preferential use of several Vβ genes and an invariant TCR α chain. J. Exp. Med. 178, 1–16 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

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

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Gras, S. et al. T cell receptor recognition of CD1b presenting a mycobacterial glycolipid. Nat. Commun. 7, 13257 (2016).

    ADS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Melandri, D. et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nat. Immunol. 19, 1352–1365 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Castro, C. D., Luoma, A. M. & Adams, E. J. Coevolution of T-cell receptors with MHC and non-MHC ligands. Immunol. Rev. 267, 30–55 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Linehan, J. L. et al. Non-classical immunity controls microbiota impact on skin immunity and tissue repair. Cell 172, 784–796 (2018). This paper demonstrates the role of H2-M3-restricted T cell responses in regulating the microbiota and wound healing in the skin.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Grant, E. J. et al. The unconventional role of HLA-E: the road less traveled. Mol. Immunol. 120, 101–112 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    McDonald, B. D., Bunker, J. J., Ishizuka, I. E., Jabri, B. & Bendelac, A. Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ+CD4CD8β intraepithelial lymphocyte lineage. Immunity 41, 219–229 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Mayans, S. et al. αβT cell receptors expressed by CD4CD8αβ intraepithelial T cells drive their fate into a unique lineage with unusual MHC reactivities. Immunity 41, 207–218 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Park, S. H. et al. Selection and expansion of CD8α/α1 T cell receptor α/β1 intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules. J. Exp. Med. 190, 885–890 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Gherardin, N. A., McCluskey, J., Rossjohn, J. & Godfrey, D. I. The diverse family of MR1-restricted T cells. J. Immunol. 201, 2862–2871 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Le Nours, J. et al. A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1. Science 366, 1522–1527 (2019).

    ADS  PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Garcia, K. C. et al. An αβ T cell receptor structure at 2.5 A and its orientation in the TCR–MHC complex. Science 274, 209–219 (1996).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Garboczi, D. N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Beringer, D. X. et al. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. Nat. Immunol. 16, 1153–1161 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Gras, S. et al. Reversed T cell receptor docking on a major histocompatibility class I complex limits involvement in the immune response. Immunity 45, 749–760 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    La Gruta, N. L., Gras, S., Daley, S. R., Thomas, P. G. & Rossjohn, J. Understanding the drivers of MHC restriction of T cell receptors. Nat. Rev. Immunol. 18, 467–478 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  64. 64.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Saunders, P. M. et al. A bird’s eye view of NK cell receptor interactions with their MHC class I ligands. Immunol. Rev. 267, 148–166 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Hoare, H. L. et al. Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat. Immunol. 7, 256–264 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Borg, N. A. et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448, 44–49 (2007). This paper provides the first insights into how unconventional TCR recognition differs from that of conventional TCRs in the form of type I NKT TCR–CD1d–lipid complex.

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

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

    ADS  PubMed  Article  CAS  PubMed Central  Google Scholar 

  71. 71.

    Eckle, S. B. G. et al. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. J. Exp. Med. 211, 1585–1600 (2014).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Patel, O. et al. Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat. Immunol. 13, 857–863 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Girardi, E. et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat. Immunol. 13, 851–856 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Gherardin, N. A. et al. Diversity of T cells restricted by the MHC class I-related molecule MR1 facilitates differential antigen recognition. Immunity 44, 32–45 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Wun, K. S. et al. T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nat. Immunol. 19, 397–406 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Bendelac, A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Seach, N. et al. Double-positive thymocytes select mucosal-associated invariant T cells. J. Immunol. 191, 6002–6009 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008). This paper demonstrates the critical role of PLZF in the effector programming of unconventional T cells such as NKT cells and MAIT cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Koay, H.-F. et al. A divergent transcriptional landscape underpins the development and functional branching of MAIT cells. Sci. Immunol. 4, eaay6039 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Griewank, K. et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 27, 751–762 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Urdahl, K. B., Sun, J. C. & Bevan, M. J. Positive selection of MHC class Ib-restricted CD8+ T cells on hematopoietic cells. Nat. Immunol. 3, 772–779 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Bediako, Y. et al. SAP is required for the development of innate phenotype in H2-M3-restricted CD8+ T cells. J. Immunol. 189, 4787–4796 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    McDonald, B. D., Jabri, B. & Bendelac, A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 18, 514–525 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Wei, D. G. et al. Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J. Exp. Med. 202, 239–248 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Guy-Grand, D. et al. Origin, trafficking, and intraepithelial fate of gut-tropic T cells. J. Exp. Med. 210, 1839–1854 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Constantinides, M. G. et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 366, eaax6624 (2019). This paper demonstrates that there is a window in early life for the colonization of tissues by MAIT cells and stresses the role of MAIT cells in wound repair.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Mazzarino, P. et al. Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion. Eur. J. Immunol. 35, 3240–3247 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Doorduijn, E. M. et al. T cells engaging the conserved MHC class Ib molecule Qa-1b with TAP-independent peptides are semi-invariant lymphocytes. Front. Immunol. 9, 60 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Havran, W. L. & Allison, J. P. Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors. Nature 344, 68–70 (1990).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Benlagha, K., Weiss, A., Beavis, A., Teyton, L. & Bendelac, A. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J. Exp. Med. 191, 1895–1904 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Loh, L. et al. Human mucosal-associated invariant T cells in older individuals display expanded TCRαβ clonotypes with potent antimicrobial responses. J. Immunol. 1950, 1119–1133 (2020).

    Article  CAS  Google Scholar 

  97. 97.

    Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997–1003 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Hinks, T. S. C. et al. Activation and in vivo evolution of the MAIT cell transcriptome in mice and humans reveals tissue repair functionality. Cell Rep. 28, 3249–3262.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Legoux, F., Salou, M. & Lantz, O. Unconventional or preset αβ T cells: evolutionarily conserved tissue-resident T cells recognizing nonpeptidic ligands. Annu. Rev. Cell Dev. Biol. 33, 511–535 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Guy-Grand, D., Cuénod-Jabri, B., Malassis-Seris, M., Selz, F. & Vassalli, P. Complexity of the mouse gut T cell immune system: identification of two distinct natural killer T cell intraepithelial lineages. Eur. J. Immunol. 26, 2248–2256 (1996). This paper provides the first evidence that intestinal tissue-resident unconventional intraepithelial T lymphocytes express NK receptors and mediate NK-cell-like killing.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Groh, V. et al. Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB. Proc. Natl Acad. Sci. USA 96, 6879–6884 (1999).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Pamer, E. G., Bevan, M. J. & Lindahl, K. F. Do nonclassical, class Ib MHC molecules present bacterial antigens to T cells? Trends Microbiol. 1, 35–38 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  106. 106.

    Gaya, M. et al. Initiation of antiviral B cell immunity relies on innate signals from spatially positioned NKT cells. Cell 172, 517–533 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994). This paper was the first study to propose that TCRγδ T cells have a role in wound healing.

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771–783 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Turtle, C. J. et al. Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161hi CD8α+ semi-invariant T cells. Blood 118, 2752–2762 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Slichter, C. K. et al. Distinct activation thresholds of human conventional and innate-like memory T cells. JCI Insight 1, e86292 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Wesley, J. D., Tessmer, M. S., Chaukos, D. & Brossay, L. NK cell-like behavior of Vα14i NK T cells during MCMV infection. PLoS Pathog. 4, e1000106 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Tyznik, A. J. et al. Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals. J. Immunol. 181, 4452–4456 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat. Immunol. 9, 146–154 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Strid, J., Sobolev, O., Zafirova, B., Polic, B. & Hayday, A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–1297 (2011).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Wu, Y. et al. An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci. Transl. Med. 11, eaax9364 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Carnaud, C. et al. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J. Immunol. 163, 4647–4650 (1999).

    CAS  PubMed  Google Scholar 

  118. 118.

    Godfrey, D. I., Le Nours, J., Andrews, D. M., Uldrich, A. P. & Rossjohn, J. Unconventional T cell targets for cancer immunotherapy. Immunity 48, 453–473 (2018).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Crowther, M. D. et al. Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat. Immunol. 21, 178–185 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Edholm, E.-S., Banach, M. & Robert, J. Evolution of innate-like T cells and their selection by MHC class I-like molecules. Immunogenetics 68, 525–536 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Mondot, S., Boudinot, P. & Lantz, O. MAIT, MR1, microbes and riboflavin: a paradigm for the co-evolution of invariant TCRs and restricting MHCI-like molecules? Immunogenetics 68, 537–548 (2016).

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Boudinot, P. et al. Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals. Proc. Natl Acad. Sci. USA 113, E2983–E2992 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Flajnik, M. F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Van Rhijn, I., Ly, D. & Moody, D. B. CD1a, CD1b, and CD1c in immunity against mycobacteria. Adv. Exp. Med. Biol. 783, 181–197 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  126. 126.

    van Wilgenburg, B. et al. MAIT cells contribute to protection against lethal influenza infection in vivo. Nat. Commun. 9, 4706 (2018).

    ADS  PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Legoux, F. et al. Microbial metabolites control the thymic development of mucosal-associated invariant T cells. Science 366, 494–499 (2019).

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Fischer, A. Severe combined immunodeficiencies. Immunodefic. Rev. 3, 83–100 (1992).

    CAS  PubMed  Google Scholar 

  129. 129.

    Barreiro, L. B. et al. Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet. 5, e1000562 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Barreiro, L. B. & Quintana-Murci, L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat. Rev. Genet. 11, 17–30 (2010).

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Howson, L. J. et al. Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1. Sci. Immunol. 5, eabc9492 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Harsha Krovi, S. et al. Thymic iNKT single cell analyses unmask the common developmental program of mouse innate T cells. Nat. Commun. 11, 6238 (2020).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Constantinides, M. G., McDonald, B. D., Verhoef, P. A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Kabelitz, D. et al. The primary response of human γ/δ+ T cells to Mycobacterium tuberculosis is restricted to Vγ9-bearing cells. J. Exp. Med. 173, 1331–1338 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Nish, S. & Medzhitov, R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 34, 629–636 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Borbulevych, O. Y., Santhanagopolan, S. M., Hossain, M. & Baker, B. M. TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. J. Immunol. 187, 2453–2463 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Wun, K. S. et al. Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. J. Biol. Chem. 287, 39139–39148 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank D. Littler for generating Fig. 1; A. Bendelac for sharing his insights on innate-like lymphocytes; D. Guy-Grand for sharing her insights on intraepithelial lymphocytes over many years; and M. Kronenberg and K. Sangani for discussions. This Review was supported by grants to B.J. from the National Institutes of Health (NIH: R01 DK67180 and R01 DK098435) and the Digestive Diseases Research Core Center at the University of Chicago (P30 DK42086); to J.R. from the Australian ARC Laureate Fellowship; and to L.B.B. from NIH: R01 GM134376.

Author information

Affiliations

Authors

Contributions

B.J. conceived the writing of the article. T.M. and B.J. conceptualized the framework and wrote the article, with input from J.R. on the ‘Modes of ligand recognition’ section and input from L.B.B. on the ‘Evolution and redundancy’ section. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Bana Jabri.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Laurent Gapin, Paul Klenerman and Laura Mackay for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mayassi, T., Barreiro, L.B., Rossjohn, J. et al. A multilayered immune system through the lens of unconventional T cells. Nature 595, 501–510 (2021). https://doi.org/10.1038/s41586-021-03578-0

Download citation

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing