Cutting edge: a single MHC anchor residue alters the conformation of a peptide-MHC complex inducing T cells that survive negative selection.
We generated transgenic mice that expressed hen egg-white lysozyme (HEL) under a class II MHC promoter. The A7 line expressed HEL with a point mutation in the Asp(52) residue, the main anchor amino acid responsible for the selection of the chemically dominant family of peptides (52-60) by I-A(k) molecules. Mice expressing HEL with Ala(52) were completely unresponsive when immunized with the same protein, i.e., HEL A52. However, the same mice immunized with wild-type HEL elicited T cells that recognized a conformation of the 52-61 core sequence uniquely different between Asp(52) and Ala(52) containing peptides. Importantly, some T cells also recognized the HEL A52 peptide given exogenously but not the same peptide processed from HEL A52 protein. Thus, a core MHC anchor residue influences markedly the specificity of the T cells. We discuss the relevance of these findings to autoimmunity and vaccination with altered peptides.
Peterson
D A
DA
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
DiPaolo
R J
RJ
Kanagawa
O
O
Unanue
E R
ER
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009113:Muramidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D017354:Point Mutation; D011487:Protein Conformation; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; C111388:I-Ak antigen; D046911:Macromolecular Substances; D010446:Peptide Fragments; D001224:Aspartic Acid; C421864:hen egg lysozyme; D009113:Muramidase; D000409:Alanine