The P9 peptide sidechain specificity of I-Ad.
The murine MHC class II variant I-Ad confers susceptibility to herpes simplex virus (HSV)-induced keratitis and relative protection against type 1 diabetes mellitus. The association to these autoimmune diseases appears to be largely determined by the peptide sidechain specificity of the P9 pocket, which we therefore have analyzed in detail. Assessment of T-cell responses and I-Ad binding capacity of position 446-substituted analogs of an IgG2a allotype b (IgG2a(b)) heavy chain peptide demonstrates that engagement of the P9 pocket is crucial for effective peptide presentation. Sidechain size rather than charge decides the capacity to engage the P9 pocket. Thus, small, uncharged sidechains are accepted, whereas acidic and aromatic amino acids as well as lysine and arginine are disfavored. The specificity of the P9 pocket of I-Ad (serine beta57) is distinct from that of the diabetes-associated I-Ag7 (aspartic acid beta57), supporting the contention that the polymorphism at residue beta57 influences diabetes susceptibility via P9-specific effects on the repertoires of self peptides presented to T cells. Furthermore, the data rationalize the susceptibility to HSV-induced keratitis conferred by the a and the protection conferred by the b allotypes of the IgG2a heavy chain. Keratitogenic T cells, which cross-react with the viral UL6 protein and a corneal antigen, are silenced in IgG2a(b) mice because of antigenic mimicry with gamma2a(b) 435-451. Our finding that the lysine P9 residue of the corresponding gamma2a(a) allopeptide precludes high-affinity binding to I-Ad indicates that the susceptibility of IgG2a(a) mice reflects inefficient thymic presentation of autologous IgG2a and thus failure to purge the T-cell repertoire of the pathogenic clones.
Bartnes
K
K
Department of Immunology, Institute of Medical Biology, University of Tromsø, School of Medicine, Norway. bartne@online.no
Li
X
X
Briand
J P
JP
Travers
P J
PJ
Hannestad
K
K
D000818:Animals; D017951:Antigen Presentation; D001224:Aspartic Acid / Q000235:genetics; D002213:Capsid / Q000276:immunology*; D036022:Capsid Proteins; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D016849:Keratitis, Herpetic / Q000276:immunology*; D051379:Mice; D009842:Oligopeptides / Q000276:immunology*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins
D036022:Capsid Proteins; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D009842:Oligopeptides; D014764:Viral Proteins; C069185:DNA cleavage and packaging proteins, Herpesvirus; D001224:Aspartic Acid