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.

Fig. 1 |. Comparison of TCR docking modes.

Experimentally determined TCR-binding modes are shown as cartoon representations for a selection of MHC class I or class I-like antigen-presenting molecules. In each panel the MHC-I subunit or equivalent is coloured as follows: light grey (HLA-A2), white (HLA-E), dark grey (MR1), light blue (CD1a), steel (CD1b), light pink (CD1c) or blue-white (CD1d). The respective antigens are coloured pink and associated β2-microglobulin orange; the interacting TCR subunits are coloured either blue (α-subunit) and green (β-subunit) or purple (δ-subunit) and lemon (γ-subunit). Below each structure is a surface representation of the antigen-presenting MHC-I molecules coloured according to their TCR subunit-recognition surfaces. a, Conventional versus unconventional ligand recognition. From left to right: a tumour-associated MART-peptide antigen in complex with HLA-A2 or HLA-E in complex with an αβTCR^,; MR1-presenting vitamin metabolites recognized by a MAIT TCR, a diverse αβTCR and CD1d in complex with type I and type II NKT TCRs. b, Breaking the TCR co-recognition paradigm. From left to right: an autoreactive αβTCR in complex with a self-lipid presented by CD1a; CD1b in complex with a mycobacterial lipid recognized by a GEM TCR; and an autoreactive TCR recognizing CD1c. c, Redundancy of ligand recognition by alternative unconventional T cell subsets. The diversity of γδTCR recognition is shown with a CD1d-reactive γδTCR using a relatively standard docking mode (left) or the more radical recognition of the underside of MR1 (right).

Fig. 2 |. Classification of non-classical T cells on the basis of central or peripheral development.

Unconventional T cells can be broadly separated into three groups largely based on their selection and differentiation patterns and how that affects their acquisition of effector programs. Group I unconventional T cells, which are classified by their acquisition of effector functions in the thymus, include NKT, MAIT and H2-M3-restricted T cells, and DETCs. Uniquely for NKT, MAIT and H2-M3-restricted T cells, this process takes place on double-positive thymocytes and requires the SAP pathway. These cells ultimately seed tissues such as the skin and liver, in which they exert their effector functions. Group II unconventional T cells include BTNL-reactive TCRγδ T cells, which leave the thymus naive and acquire effector functions in the periphery on tissue-specific self-ligands. Finally, group III unconventional T cells follow the conventional T cell path by leaving the thymus naive and only acquire effector functions once they encounter their cognate foreign antigen in the periphery. Grey cells represent naive T cells; different coloured cells represent effector T cells.

Fig. 3 |. Functional niche of unconventional T cells.

The T cell compartment is shown on a gradient from conventional T cells (right) to unconventional T cell subsets (left) according to the classifiers in bold. Classical adaptive T cells occupy a specific niche in terms of the antigenic universe they recognize (that is, MHC–peptide complexes), and they colonize tissues as tissue-resident memory T cells (T_RM) only after being activated and having expanded in peripheral lymph nodes in response to an infection. By contrast, unconventional T cells recognize a broad spectrum of antigens ranging from self-molecules, to microbial extended self and non-self, to formylated peptides and to peptides. The clonal size at homeostasis for unconventional T cell subsets like NKT, MAIT and BTNL-reactive TCRγδ T cells is large, as these cells expand in tissues early in life and in the case of NKT and MAIT cells can occupy multiple tissues. The role of innate immune signals versus TCR-mediated signals varies in the activation of the different unconventional T cell subsets; innate signals have a more critical role in the innate-like unconventional T cells that expand and acquire an effector phenotype either in response to self in the periphery (BTNL-reactive TCRγδ T cells) or in the thymus during their development (MR1-, CD1d- and H2-M3-restricted T cells) than in HLA-E-restricted T cells that become activated in the periphery, similarly to conventional T cells. Of note, tissue-resident memory T cells also acquire the ability to respond to innate signals after establishing residence in tissues and are distinct in that regard from circulating memory and effector memory T cells. Finally, the unconventional T cell compartment constitutes a primary line of defence and also has an important role in tissue homeostasis and healing.

Fig. 4 |. Conservation and redundancy within the T cell compartment.

a, The selective constraint score shown (filled circles) is the ratio of the observed versus the expected (o/e) number of loss-of-function variants in that gene in the general population. The o/e metric comes with a 90% confidence interval, which is shown by the dashed lines. When a gene has a low o/e value, it is under stronger selection against loss-of-function mutations than a gene with a higher value. Genes were grouped into five major biological groups on the basis of their function and ranked from the most selectively constrained to the least constrained. The scores were obtained from the Genome Aggregation Database (gnomAD, v.2.1.1) and are based on sequencing data from 25,748 exome sequences and 15,708 whole-genome sequences from unrelated individuals. b, This figure shows that ZAP70 has a central role in the signalling hub of all T cells and, using MAIT and NKT cells as an example of unconventional T cell subsets, illustrates the multifaceted nature of the immune system that has evolved to have multiple conventional and unconventional T cell subsets that mediate the same key effector functions. Although there is redundancy at this functional level, these T cell subsets have different modes of recognition and are regulated by different stimuli, thereby increasing the robustness and resilience of the immune system. This property of the immune system also underlies the difficulty of showing a requirement for any given unconventional T cell subset. T_H1, T helper 1 cell; T_H2, T helper 2 cell; T_H17, T helper 17 cell.