Mucosal‐associated invariant T cell receptor recognition of small molecules presented by MR1

Abstract

The major histocompatibility complex (MHC) class-I related molecule MR1 is a monomorphic and evolutionary conserved antigen (Ag)-presenting molecule that shares the overall architecture of MHC-I and CD1 proteins. However, in contrast to MHC-I and the CD1 family that present peptides and lipids, respectively, MR1 specifically presents small organic molecules. During microbial infection of mammalian cells, MR1 captures and presents vitamin B precursors, derived from the microbial biosynthesis of riboflavin, on the surface of antigen-presenting cells. These MR1-Ag complexes are recognized by the mucosal-associated invariant T cell receptor (MAIT TCR), which subsequently leads to MAIT cell activation. Recently, MR1 was shown to trap chemical scaffolds including drug and drug-like molecules. Here, we review this metabolite Ag-presenting molecule and further define the key molecular interactions underlying the recognition and reactivity of MAIT TCRs to MR1 in an Ag-dependent manner.

Chronically stimulated human MAIT cells are unexpectedly potent IL‐13 producers

“…They recognize riboflavin metabolites (e.g. 5‐[2‐oxopropylideneamino]‐6‐D‐ribitylaminouracil (5‐OP‐RU)) produced by bacteria and yeast, although MAIT cells can also be stimulated independently of the TCR by interleukin (IL)‐12 and IL‐18, which are associated with microbial infection . Human MAIT cells are abundant in mucosal tissues such as the lung and colon and also comprise approximately 5% of T cells in peripheral blood …”

The Diverse Family of MR1-Restricted T Cells

“…The extent to which these different Ags exist in nature remains unclear, nonetheless their unifying feature is the conserved ribityl tail that is directly recognized by the MAIT TCR upon docking with MR1 [(43) and reviewed in Ref. 44)]. Beyond riboflavin-based Ags, vitamin B2 (folate) derivatives can also be captured and presented by MR1, including the folate photodegradation product 6-FP (6) and its synthetic derivative acetyl 6-FP (Ac-6-FP) (45).…”

“…Ag-specific MAIT cell subsets. Extensive x-ray crystallography studies have shown that MAIT TCRs conform to a pattern recognition-like docking mode atop MR1, whereby the germline-encoded CDR1 and 2 loops of the TCR aand b-chains straddle the a2 and a1 helices of MR1, respectively, placing the invariant CDR3a loop in a conserved position extending into the Ag-binding pocket of MR1 (43,44,47). This allows CDR3a to interact directly with the ribityl tail of riboflavin-based Ags, with the sole contact being mediated by a TRAJ gene-encoded tyrosine at position 95 of the TCR a-chain (Tyr95a; Fig.…”

MAIT cells: the end of the beginning?

“…1 This leads naturally on from the cells themselves to what they recognizea major set of discoveries which has led to an explosion of interest in the field. 2,3 The development of this cell type and its selection in the thymus is next explored, an area that can give insight into not only MAIT cell biology but that of other related cell types. 4 The last three reviews look further into the biological roles of these cells.…”

“…The Special Feature reviews in this issue start with the historical perspective on MAIT cells – in terms of both their discovery and their evolution – which may give some clue as to their critical and overlapping functions . This leads naturally on from the cells themselves to what they recognize – a major set of discoveries which has led to an explosion of interest in the field . The development of this cell type and its selection in the thymus is next explored, an area that can give insight into not only MAIT cell biology but that of other related cell types .…”