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Elsevier BV Journal of Biological Chemistry 301(8)
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    초록·키워드

    Mucosal-associated invariant T (MAIT) cells express a TRAV1-2<sup>+</sup> T-cell receptor (TCR) that recognizes microbial vitamin B2 derivatives presented by the major histocompatibility complex class I-related molecule (MR1). Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilize other trbv genes, including TRBV28. A second conserved, albeit less frequent TRAV36<sup>+</sup> TRBV28<sup>+</sup> T-cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1-antigen (Ag) recognition compared with MAIT TCR-MR1 binding. Nevertheless, our understanding of how differing TCR gene usage results in altered MR1 binding modes remains incomplete. Here, binding studies demonstrated differential affinities and Ag specificities between TRBV6<sup>+</sup> and TRBV28<sup>+</sup> MR1-restricted TCRs. Alanine-scanning mutagenesis on the TRAV36-TRBV28 TCR revealed a strong dependence on germline-encoded residues within the highly selected complementarity-determining region 3α loop, similar to TRAV1-2-TRBV6 TCRs, and further alanine-scanning mutagenesis experiments demonstrate differential energetic footprints by these TCRs atop MR1. We determined the crystal structure of a MAIT TRAV1-2-TRBV28<sup>+</sup> TCR-MR1-5-OP-RU ternary complex. This structure revealed a docking mode conserved amongst other TRAV1-2<sup>+</sup> MAIT TCRs, with the trbv28-encoded TCR-β chain adopting highly distinct docking modes between the TRAV1-2<sup>+</sup> and TRAV36<sup>+</sup> TCRs. This indicates that the TCR-α chain dictates the positioning and role of the TCR-β chain. Taken together, these findings provide new molecular insights into MR1-Ag-driven selection of paired TCR-α and TCR-β chains.

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