title: The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Adam L
authors.initials: AL
authors.lastname: Corper
authors.forename: Rana
authors.initials: R
authors.lastname: Herro
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
mesh_terms: D000818:Animals; D002469:Cell Separation; D018360:Crystallography, X-Ray / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D019281:Dimerization; D005260:Female; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000502:physiology; D006801:Humans; D006825:Hybridomas / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D011948:Receptors, Antigen, T-Cell
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