T-lymphocyte response to cytochrome c. I. Demonstration of a T-cell heteroclitic proliferative response and identification of a topographic antigenic determinant on pigeon cytochrome c whose immune recognition requires two complementing major histocompatibility complex-linked immune response genes.

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Abstract
The T[thymus-derived]-lymphocyte proliferative response to pigeon cytochrome c was studied in the mouse. H-2a and H-2k strains were responders to this antigen whereas H-2b, H-2d, H-2f, H-2ja, H-2p, H-2q, H-2r, H-2s and H-2u strains were low or nonresponders. Genetic mapping demonstrated that 2 major histocompatibility complex (MHC)-linked Ir genes control the response, in I-A, the other in I-E/I-C. The major antigenic determinant recognized in this response was localized by cross-stimulations with species variants and cyanogen bromide cleavage fragments of cytochrome c. The antigenic determinant was a topographic surface determinant composed of an Ile for Val substitution at residue 3, a Gln for Lys substitution at residue 100 and a lys for Glu substitution at residue 104. Tobacco hornworm moth cytochrome c, which contains a Gln at residue 100 but a terminal Lys at residue 103 (1 amino acid closer to the Gln), stimulated pigeon cytochrome c immune T cells better than the immunogen. This is the 1st demonstration of a functional T-cell heteroclitic proliferative response in a system under Ir gene control. Immunization with the cyanogen bromide cleavage fragments revealed that only pigeon cytochrome c fragment 81-104 was immunogenic. This fragment primed for a T-cell proliferative response whose specificity was nearly identical to that of the T-cell response primed for by the whole molecule, suggesting that the Gln at 100 and lys at 104 form the immunodominant portion of the antigenic site. Mixing experiments using the 2 cross-reacting antigens, hippopotamus cytochrome c and Pekin duck or chicken cytochrome c fragment (81-104), each of which contains only 1 of the 2 immunodominant substitutions, demonstrated that the T lymphocytes responding to the major antigenic determinant comprise a single family of clones that recognize both amino acids as part of the same determinant. Two complementing MHC-linked Ir genes can control the immune response to a single antigenic determinant.

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