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Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop

Author

Listed:
  • Dhruv K. Sethi

    (Dana-Farber Cancer Institute)

  • Susana Gordo

    (Dana-Farber Cancer Institute)

  • David A. Schubert

    (Dana-Farber Cancer Institute)

  • Kai W. Wucherpfennig

    (Dana-Farber Cancer Institute
    Program in Immunology, Harvard Medical School)

Abstract

Self-reactive CD4 T cells are thought to have a central role in the pathogenesis of many chronic inflammatory human diseases. Microbial peptides can activate self-reactive T cells, but the structural basis for such crossreactivity is not well understood. The Hy.1B11 T cell receptor (TCR) originates from a patient with multiple sclerosis and recognizes the self-antigen myelin basic protein. Here we report the structural mechanism of TCR crossreactivity with two distinct peptides from human pathogens. The structures show that a single TCR residue (CDR3α F95) makes the majority of contacts with the self-peptide and both microbial peptides (66.7–80.6%) due to a highly tilted TCR-binding topology on the peptide-MHC surface. Further, a neighbouring residue located on the same TCR loop (CDR3α E98) forms an energetically critical interaction with the MHC molecule. These data show how binding by a self-reactive TCR favors crossreactivity between self and microbial antigens.

Suggested Citation

  • Dhruv K. Sethi & Susana Gordo & David A. Schubert & Kai W. Wucherpfennig, 2013. "Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3623
    DOI: 10.1038/ncomms3623
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