Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity

Jarrett J. Adams, Samanthi Narayanan, Michael E. Birnbaum, Sachdev S. Sidhu, Sydney J. Blevins, Marvin H. Gee, Leah V. Sibener, Brian M. Baker, David M. Kranz, K. Christopher Garcia

Research output: Contribution to journalArticlepeer-review

Abstract

The T cell antigen receptor (TCR)-peptide-major histocompatibility complex (MHC) interface is composed of conserved and diverse regions, yet the relative contribution of each in shaping recognition by T cells remains unclear. Here we isolated cross-reactive peptides with limited homology, which allowed us to compare the structural properties of nine peptides for a single TCR-MHC pair. The TCR's cross-reactivity was rooted in highly similar recognition of an apical 'hot-spot' position in the peptide with tolerance of sequence variation at ancillary positions. Furthermore, we found a striking structural convergence onto a germline-mediated interaction between the TCR CDR1α region and the MHC α2 helix in twelve TCR-peptide-MHC complexes. Our studies suggest that TCR-MHC germline-mediated constraints, together with a focus on a small peptide hot spot, might place limits on peptide antigen cross-reactivity.

Original languageEnglish (US)
Pages (from-to)87-94
Number of pages8
JournalNature Immunology
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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