Hindrance of binding to class II major histocompatibility complex molecules by a single amino acid residue contiguous to a determinant leads to crypticity of the determinant as well as lack of response to the protein antigen.
The immune system has evolved the potential to respond to a wide variety of antigens, yet unresponsiveness to many foreign determinants is encountered frequently. Here, we report a lack of response to a particular determinant, hen egg lysozyme (HEL)-(46-61)-peptide (p46-61), in C57BL/6 (H-2b) mice, whereas a strong T-cell response to this determinant is obtained in major histocompatibility complex (MHC)-identical C3H.SW mice. However, (C3H.SW x C57BL/6)F1 mice respond well to p46-61, suggesting the absence of a p46-61-specific "hole" in the T-cell repertoire in C57BL/6 mice. We further show that p46-61 cannot bind the I-Ab class II MHC molecule, whereas p46-60 lacking Arg61 exhibits good binding and is immunogenic in both strains. Thus, the presence of the hindering residue, Arg61, renders p46-61, a dominant determinant in C3H.SW, into a silent, cryptic determinant in C57BL/6 mice. Upon i.p. immunization with HEL, no T-cell responses to either HEL or p46-61 could be demonstrated in spleens of HEL-primed C57BL/6 mice, whereas a predominant response to p46-61 and HEL was demonstrated in C3H.SW mice. Evidently, C57BL/6 mice differ from C3H.SW in their ability to process p46-61 into an actual I-Ab binding determinant, indicating a putative enzymatic defect in the C57BL/6 strain. Furthermore, our results suggest that the inability of C57BL/6 mice to respond in the spleen to HEL is based upon its failure to generate a dominant immunogenic determinant from HEL, coupled with its pattern of susceptibility to regulatory effects.
Grewal
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IS
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024-1489.
Moudgil
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KD
Sercarz
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EE
D000595:Amino Acid Sequence; D000818:Animals; D000939:Epitopes; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009113:Muramidase / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology
D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D009113:Muramidase