Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers

Abstract

Rahimpour et al. use MR1 tetramers to characterize the heterogeneous population of mouse MAIT cells and find a close resemblance to their human counterparts. These findings will provide the foundation for further investigation of MAIT cells in health and disease.

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

“…MAIT cells display an intrinsic effector‐memory phenotype – i.e. without the need for prior clonal expansion14 – typically CD45RA − CD45RO + CD95 Hi CD62L Lo CD44 Hi 2, 15, 16, 17 – and can rapidly secrete a range of pro‐inflammatory cytokines including tissue necrosis factor‐ α (TNF‐ α ), interleukin‐17 (IL‐17) and interferon‐ γ (IFN‐ γ ), and also the type 2 cytokine IL‐4 on TCR ligation 15, 17. 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.…”

“…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.…”

“…In both species MAIT cells express orthologous TCR‐ α chains, are MR1 restricted and recognize the same antigen. In both species MAIT cells express the master transcription factor PLZF and signature surface markers including CD127 (IL7R α ), CD218 (IL18R α ), CCR9 and CCR6 17. However, by contrast, MAIT cells are at least 10‐fold less abundant in mice than in humans 17, 27.…”

“…In both species MAIT cells express the master transcription factor PLZF and signature surface markers including CD127 (IL7R α ), CD218 (IL18R α ), CCR9 and CCR6 17. However, by contrast, MAIT cells are at least 10‐fold less abundant in mice than in humans 17, 27. Although some other previously reported species differences may have been artefacts of a specific transgenic murine model,17 other differences include a more limited expression of CD161 in mice17, 24 and, of relevance to this review, a difference in IL‐17 production.…”