Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells

Abstract

Generation of antigen-loaded MR1 tetramers that specifically stain MAIT cells identifies heterogeneity in phenotypes and TCR repertoires in humans and mice.

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…In co‐culture studies V α 19i T cells induced IL‐10 from iNKT cells and conventional T cells, but most potently from CD19 + B cells, and this was, at least partly, by an MR1‐independent mechanism through inducible T‐cell co‐stimulator–B7 related protein‐1 interactions. One important limitation of the methodology used in this and other16, 24, 31 studies is that the V α 19i population includes many MHC‐restricted ‘MAIT‐like’ cells that do not stain with the specific MR1 tetramer or express signature innate cell transcription factors like PLZF 17, 22. Together these findings suggest that MAIT cells are protective against autoimmune demyelinating inflammation by a suppressive effect on other B and T cells, particularly by enhancing IL‐10 secretion and inhibiting Th1 cytokines.…”

“…Although our knowledge of the emerging field of MAIT cell biology is limited, several factors implicate these cells in immune‐mediated diseases, including their pro‐inflammatory profile,40 their widespread tissue distribution and effector‐memory phenotype. However, many clinical studies to date are confounded by the effect of therapeutic steroids, and others that use a V α 7.2CD161 + definition of MAIT cells may be confounded by the down‐regulation of CD161 which occurs with chronic activation 22, 85. Moreover, most clinical data are only observational, making it hard to determine whether aberrations are primary phenomena, or perhaps represent a response to the effects of a disordered cytokine milieu 35.…”

“…Most MAIT cell TCRs comprise a semi‐invariant TCR‐ α chain – usually TRAV1‐2‐TRAJ33 (V α 7.2 − J α 33 in humans, V α 19 − J α 33 in mice),90 although in humans some MAIT cells also use TRAV1‐2‐TRAJ12 or TRAV1‐2‐TRAJ2022) – predominantly associated with the β ‐chains TRBV20 (V β 2) or TRBV6 (V β 13) in humans1 and TRBV19 (V β 6) or TRBV13 (V β 8) in mice 1, 22, 23. These preferential TCR rearrangements arise partly through a process of ‘convergent recombination’91 whereby much of the antigen specificity of MAIT cells is essentially germline‐encoded.…”

“…MAIT cells share some similarities with invariant natural killer T (iNKT) cells, which are implicated in many autoimmune conditions,18, 19 including expression of a semi‐invariant TCR, restriction by non‐classical MHC molecules, and expression of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF)20 although many differences exist, notably the nature of the ligands and the restriction molecule. Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25. A peculiarity of MAIT cell biology is that although MR1 expression is ubiquitous,3, 26 it is normally found only at very low levels on the cell surface 26, 27, 28.…”

“…Nonetheless, to date, data regarding MAIT cells in immune‐mediated disease are scant, at least partly because MAIT cells were unknown until recently and specific immunological tools, such as relevant antibodies, transgenic models16, 24, 31 and specific tetramers for humans7, 22 and mice,17 were unavailable. Furthermore, because of the limited diversity of the MAIT TCR and the non‐polymorphic, non‐human leucocyte antigen (HLA) encoded nature of MR1, it is unlikely that there will be pathological autoreactive MAIT cells leading directly to HLA‐associated diseases meeting the stringent definition of a classic autoimmune disease 32.…”