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A multilayered immune system through the lens of unconventional T cells

Nature volume 595, pages 501–510 (2021)Cite this article

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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.

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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.

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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.

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Authors and Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Toufic Mayassi

  2. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Toufic Mayassi, Luis B. Barreiro & Bana Jabri

  3. Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA

    Luis B. Barreiro

  4. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA

    Luis B. Barreiro

  5. Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Jamie Rossjohn

  6. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Jamie Rossjohn

  7. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK

    Jamie Rossjohn

  8. Department of Medicine, University of Chicago, Chicago, IL, USA

    Bana Jabri

  9. Department of Pathology, University of Chicago, Chicago, IL, USA

    Bana Jabri

  10. Department of Pediatrics, University of Chicago, Chicago, IL, USA

    Bana Jabri

Authors
  1. Toufic Mayassi
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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.

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Correspondence to Bana Jabri.

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

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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

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