The T lymphocyte response to cytochrome <i>C</i>. III. Relationship of the fine specificity of antigen recognition to major histocompatibility complex genotype.

Abstract

Abstract The fine specificity and genetic control of the murine T lymphocyte proliferative response to the globular protein antigen pigeon cytochrome c was assessed in the high responder strain, B10.S(9R) (H-2t4), and was compared to previously reported results for the B10.A (H-2a) strain. The proliferative response of T cells from both strains was shown to be controlled by two complementing major histocompatibility complex- (MHC) linked immune response (IR) genes, and required the presence of the two high responder Ir alleles in a single antigen-presenting cell. Furthermore, the proliferative responses of T cells from both strains were inhibited by a monoclonal anti-la antibody (Y-17) reactive with a common combinatorial or conformational determinant on the Ae3:Eαk (B10.S(9R)) and Aek:Eαk (B10.A) la molecules. These results suggest the T cells from B10.S(9R) and B10.A mice respond to pigeon cytochrome c in the context of homologous la molecules that are presumably encoded for by the complementing Ir genes. The antigenic determinant on pigeon cytochrome c recognized by the B10.S(9R) T cells was the same C-terminal site recognized by the B10.A. However, certain fine specificity differences in the responses of the two strains could be demonstrated. Whereas B10.A T cells were stimulated by species variant cytochromes c possessing either the immunodominant glutamine (or serine) at position 100 or the C-terminal lysine at position 103 or 104, B10.S(9R) T cells were generally stimulated only by cytochromes c bearing both of these amino acid residues. Finally, because the two strains appeared to recognize similar antigenic determinants in the context of homologous la molecules, we attempted to present pigeon cytochrome c to T cells of one strain on antigen-presenting cells from the other. Using pigeon cytochrome c-specific, long-term T cell lines to reduce alloreactivity and magnify the specific response, we were able to demonstrate up to 20% cross-presentation between the two strains. These results demonstrate that MHC restriction is not absolute, although the degree of degeneracy for even closely homologous la molecules is limited.