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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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.
The authors declare no competing interests.
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