Holes in the T cell repertoire to myelin basic protein owing to the absence of the D beta 2-J beta 2 gene cluster: implications for T cell receptor recognition and autoimmunity.
Models of T cell recognition suggest that amino acid residues in the CDR3 region of the T cell receptor (TCR) alpha or beta chain directly contact the major histocompatibility complex-bound peptide, and thus are crucial for providing peptide specificity. T cells derived from B10.PL or PL/J mice of H-2u haplotype, use only D beta 2 and J beta 2 gene segments in the recognition of the dominant determinant, Ac1-9/Au, of myelin basic protein (MBP). New Zealand White (NZW) mice, with identical class II H-2u genes (I-A and I-E), carry an 8.8-kb deletion in their TCR beta chain locus encompassing D beta 2 and J beta 2 gene segments. How does this deletion of the crucial D beta 2-J beta 2 region in NZW mice influence specific responses to Ac1-9/Au as well as to other known Au or Eu determinants of MBP? We found that these mice respond very poorly to the dominant Ac1-9/Au and to the subdominant 31-50/Eu determinant in in vitro proliferation assays as well as in their in vivo capacity to induce experimental autoimmune encephalomyelitis. This loss of response is apparently owing to the absence of high avidity TCRs with essential CDR3 residues contributed by D beta 2 or J beta 2 gene segments. These data reveal constraints in the recognition of certain antigenic structures, and further support a TCR-recognition model in which CDR3 residues of the TCR alpha and beta chains constitute the antigenic peptide-binding sites on the TCR molecule. Implications for autoimmune manifestations contributed by NZW genes in (NZB x NZW)F1 disease are also discussed.
Kumar
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V
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024-1489.
Sercarz
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E
D000818:Animals; D015551:Autoimmunity; D005260:Female; D017353:Gene Deletion; D007114:Immunization; D051379:Mice; D005810:Multigene Family; D004676:Myelin Basic Protein / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta