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

Nature Immunology volume 17, pages 8794 (2016) | Download Citation

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.

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Acknowledgements

We thank S. O'Herrin (Ben May Institute for Cancer Research) for the 58α cell line; J.M. Connolly (Washington University School of Medicine) for the LM1.8-H-2LdW97R cell line; and N. Goriatcheva, E. Özkan, D.Wittrup, E. Newell, N. Jarvik and M. McLaughlin for discussions. Supported by the Canadian Institutes of Health Research (J.J.A.), the National Science Foundation (M.E.B.), the US National Institutes of Health (AI103867, AI045757 and AI057229 to K.C.G., and GM55767 to D.M.K.), the Jordan family, and the Howard Hughes Medical Institute (K.C.G.). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the Department of Energy Office of Biological and Environmental Research and by the US National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393).

Author information

Author notes

    • Jarrett J Adams
    • , Samanthi Narayanan
    •  & Michael E Birnbaum

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute, and Departments of Molecular and Cellular Physiology, and Structural Biology, Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.

    • Jarrett J Adams
    • , Michael E Birnbaum
    • , Marvin H Gee
    • , Leah V Sibener
    •  & K Christopher Garcia
  2. Banting and Best Department of Medical Research and Department of Molecular Genetics, University of Toronto, Terrence Donnelly Centre for Cellular & Biomolecular Research, Toronto, Ontario, Canada.

    • Jarrett J Adams
    •  & Sachdev S Sidhu
  3. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

    • Samanthi Narayanan
    •  & David M Kranz
  4. Department of Chemistry & Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.

    • Sydney J Blevins
    •  & Brian M Baker

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Contributions

J.J.A., S.N., M.E.B., D.M.K. and K.C.G. conceived of the project; J.J.A., S.N., and M.E.B. performed experiments and analyzed data; and all authors interpreted data, developed the concepts in the manuscript, and wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to K Christopher Garcia.

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DOI

https://doi.org/10.1038/ni.3310