Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor

Nat Immunol. 2005 May;6(5):490-6. doi: 10.1038/ni1187. Epub 2005 Apr 10.


Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Autoantigens / chemistry
  • Autoantigens / immunology*
  • Autoimmunity / immunology*
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism
  • Complementarity Determining Regions / immunology
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / immunology
  • Histocompatibility Antigens Class II / chemistry*
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Myelin Basic Protein / chemistry
  • Myelin Basic Protein / immunology
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptides / chemistry
  • Peptides / immunology*
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / immunology*
  • Structure-Activity Relationship


  • Autoantigens
  • CD4 Antigens
  • Complementarity Determining Regions
  • Epitopes
  • Histocompatibility Antigens Class II
  • Myelin Basic Protein
  • Peptide Fragments
  • Peptides
  • Receptors, Antigen, T-Cell
  • myelin basic protein 83-99

Associated data

  • PDB/1YMM