The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity

J Clin Invest. 2010 May;120(5):1578-90. doi: 10.1172/JCI41502. Epub 2010 Apr 19.


Genetic susceptibility to autoimmunity is frequently associated with specific MHC alleles. Diabetogenic MHC class II molecules, such as human HLA-DQ8 and mouse I-Ag7, typically have a small, uncharged amino acid residue at position 57 of their beta chain (beta57); this results in the absence of a salt bridge between beta57 and Argalpha76, which is adjacent to the P9 pocket of the peptide-binding groove. However, the influence of Argalpha76 on the selection of the TCR repertoire remains unknown, particularly when the MHC molecule binds a peptide with a neutral amino acid residue at position P9. Here, we have shown that diabetogenic MHC class II molecules bound to a peptide with a neutral P9 residue primarily selected and expanded cells expressing TCRs bearing a negatively charged residue in the first segment of their complementarity determining region 3beta. The crystal structure of one such TCR in complex with I-Ag7 bound to a peptide containing a neutral P9 residue revealed that a network of favorable long-range (greater than 4 A) electrostatic interactions existed among Argalpha76, the neutral P9 residue, and TCR, which supported the substantially increased TCR/peptide-MHC affinity. This network could be modulated or switched to a lower affinity interaction by the introduction of a negative charge at position P9 of the peptide. Our results support the existence of a switch at residue beta57 of the I-Ag7 and HLA-DQ8 class II molecules and potentially link normal thymic TCR selection with abnormal peripheral behavior.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Separation
  • Crystallography, X-Ray / methods
  • Diabetes Mellitus, Experimental / genetics*
  • Dimerization
  • Female
  • Genetic Complementation Test
  • Genetic Predisposition to Disease
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / physiology
  • Humans
  • Hybridomas / pathology
  • Kinetics
  • Mice
  • Molecular Conformation
  • Receptors, Antigen, T-Cell / metabolism*
  • Thymus Gland / metabolism


  • Histocompatibility Antigens Class II
  • I-A g7 antigen
  • Receptors, Antigen, T-Cell