T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly, though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity and highlight challenges associated with predicting T cell reactivities.
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Authors were supported by NIH grants GM118166 and AI29543 (B.M.B.); CA154778 and CA153789 (M.I.N.); and AI103867 (K.C.G.); and American Cancer Society grant IRG-14-195-01 (L.M.H.). T.P.R. and J.A.A. were supported by fellowships from the Indiana CTSI, funded in part by NIH grants TR001107 and TR001108. M.H.G. was supported by a Stanford Graduate Research Fellowship and NIH grant CA216926. J.L.M. was supported by NIH grant CA175127. K.C.G. is supported by the Howard Hughes Medical Institute and the Parker Institute for Cancer Immunotherapy.
T.P.R. is employed by a new startup company that uses structural information to explore and modulate TCR specificity. B.M.B. is on the board of this company.
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Riley, T.P., Hellman, L.M., Gee, M.H. et al. T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability. Nat Chem Biol 14, 934–942 (2018). https://doi.org/10.1038/s41589-018-0130-4
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