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

Dhruv K. Sethi, Susana Gordo, David A. Schubert and Kai W. Wucherpfennig ()
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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

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3623

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