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

• Published in: Nature chemical biology Vol. 14; no. 10; pp. 934 - 942
• Main Authors: Riley, Timothy P., Hellman, Lance M., Gee, Marvin H., Mendoza, Juan L., Alonso, Jesus A., Foley, Kendra C., Nishimura, Michael I., Vander Kooi, Craig W., Garcia, K. Christopher, Baker, Brian M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2018; Nature Publishing Group
• Subjects: 631/250; 631/535/1266; 631/57; Adaptability; Antigens; Antigens - chemistry; Astrochemistry; Autoimmunity; Binding; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cross Reactions; Cross-reactivity; Crystallography, X-Ray; Epitopes - chemistry; Grooves; Homology; Humans; Kinetics; Ligands; Lymphocytes; Major histocompatibility complex; Mimicry; Molecular Mimicry; Oligopeptides - chemistry; Organic chemistry; Peptides; Physiochemistry; Predictive control; Protein Binding; Protein Domains; Reactivity; Receptors; Receptors, Antigen, T-Cell - chemistry; Retroviridae; Surface Plasmon Resonance; T cell receptors; T-Lymphocytes - chemistry
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-018-0130-4

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.
Structural analysis shows that cross-reactivity of the T cell receptor DMF5 is governed by adaptability of the peptide antigen, which can undergo TCR-binding-induced frameshifting forcing the peptide C terminus to extend from the MHC-binding groove.