Journal Article

T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability

Baker, Brian M, Riley, Timothy P, Gee, Marvin H, Alonso, Jesus A, Mendoza, Juan L, Foley, Kendra C, Hellman, Lance M, Nishimura, Michael I, Vander Kooi, Craig W, Garcia, K Christopher

2018

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adaptability / Antigens / Astrochemistry / Binding / Cross-reactivity / Grooves / Homology / Lymphocytes / Major histocompatibility complex / Mimicry / Organic chemistry / Peptides / Physiochemistry / Predictive control / Reactivity / Receptors / T cell receptors