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

Nat Commun. 2013;4:2623. doi: 10.1038/ncomms3623.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Autoantigens
  • Bacterial Proteins
  • Myelin Basic Protein
  • Receptors, Antigen, T-Cell
  • Viral Proteins