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

Publication Type:

Journal Article


Nat Commun, Volume 4, p.2623 (2013)


Amino Acid Sequence, Autoantigens, Autoimmunity, Bacterial Proteins, Binding Sites, CD4-Positive T-Lymphocytes, Cross Reactions, Crystallography, X-Ray, Humans, Models, Molecular, Molecular Sequence Data, Multiple Sclerosis, Myelin Basic Protein, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Pseudomonas aeruginosa, Receptors, Antigen, T-Cell, Sequence Alignment, Sequence Homology, Amino Acid, Simplexvirus, Viral Proteins


<p>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. </p>