Abstract
Mucosal-associated invariant T (MAIT) cells are thought to detect microbial antigens presented by the HLA-Ib molecule MR1 through the exclusive use of a TRAV1-2-containing TCRα. Here we use MR1 tetramer staining and ex vivo analysis with mycobacteria-infected MR1-deficient cells to demonstrate the presence of functional human MR1-restricted T cells that lack TRAV1-2. We characterize an MR1-restricted clone that expresses the TRAV12-2 TCRα, which lacks residues previously shown to be critical for MR1-antigen recognition. In contrast to TRAV1-2+ MAIT cells, this TRAV12-2-expressing clone displays a distinct pattern of microbial recognition by detecting infection with the riboflavin auxotroph Streptococcus pyogenes. As known MAIT antigens are derived from riboflavin metabolites, this suggests that TRAV12-2+ clone recognizes unique antigens. Thus, MR1-restricted T cells can discriminate between microbes in a TCR-dependent manner. We postulate that additional MR1-restricted T-cell subsets may play a unique role in defence against infection by broadening the recognition of microbial metabolites.
Highlights
Mucosal-associated invariant T (MAIT) cells are thought to detect microbial antigens presented by the HLA-Ib molecule MR1 through the exclusive use of a TRAV1-2-containing TCRa
MAIT cells can detect a wide range of bacteria and fungi through recognition of riboflavin metabolites presented by the HLA-Ib molecule MR1
While MAIT cells have been defined through their usage of the TRAV1-2 T-cell antigen receptor (TCR), in this report we demonstrate unambiguously the presence of MR1-restricted T cells that are TRAV1-2-negative, demonstrate the specific usage of the TRAV12-2 TCR by a clone and find that these cells are capable of recognizing both the previously demonstrated RL riboflavin intermediates, as well as unique ligands derived from S. pyogenes, a bacterium incapable of riboflavin biosynthesis
Summary
Mucosal-associated invariant T (MAIT) cells are thought to detect microbial antigens presented by the HLA-Ib molecule MR1 through the exclusive use of a TRAV1-2-containing TCRa. We previously evaluated the ex vivo human TCR repertoire of MAIT cells responsive to three riboflavin-synthesizing microbes[23], finding that distinct MAIT TCR usage was associated with microbeselective responses within and across individuals These data support the hypothesis that MR1 can present discrete microbial ligands, and that this presentation is in turn associated with selective clonal expansion of MAIT cells. It is not known whether each microbe synthesizes the same repertoire of riboflavin metabolites, but at varying proportions, or whether there are unique ligands. These findings suggest that MR1-restricted T cells could use diverse TCRs to recognize microbial infection; the full repertoire of TCRs that can be used by MR1-restricted T cells is unknown
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