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.
