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.

Abstract

The T-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 two major histocompatibility complex (MHC)-linked Ir genes control the response, one 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. It was found to be a topographic surface determinant composed of an isoleucine for valine substitution at residue 3, a glutamine for lysine substitution at residue 100 and a lysine for glutamic acid substitution at residue 104. Tobacco hornworm moth cytochrome c, which contains a glutamine at residue 100 but a terminal lysine at residue 103 (one amino acid closer to the glutamine), stimulated pigeon cytochrome c immune T cells better than the immunogen. This result demonstrates for the first time 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 glutamine at 100 and the lysine at 104 form the immunodominant portion of the antigenic site. Furthermore, mixing experiments using the two cross-reacting antigens, hippopotamus cytochrome c and Pekin duck or chicken cytochrome c fragment (81-104), each of which contains only one of the two 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. Thus, two complementing MHC-linked Ir genes can control the immune response to a single antigenic determinant.

A Single Heteroclitic Epitope Determines Cancer Immunity After Xenogeneic DNA Immunization Against a Tumor Differentiation Antigen

“…A heteroclitic epitope describes an altered peptide that is a better agonist for inducing T cell responses than the native, unaltered peptide (13). This terminology has been applied to other altered peptides with a higher immunological potency than their unaltered counterparts (14 -16).…”

The Study of High-Affinity TCRs Reveals Duality in T Cell Recognition of Antigen: Specificity and Degeneracy

“…ϩ T cells used model Ags, such as pigeon cytochrome c or hen egg-white lysozyme (5,6). Purified proteins from different animal species of cytochrome or lysozyme with known sequences were then tested for their ability to crossstimulate T cells.…”

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

“…In rodents, short peptide sequences derived from the α 1 domain polymorphic region of rat class I RT1.A a induced sensitization against RT1 a allografts [12], provoked alloantibody production and T cell proliferative responses [13][14][15]. MHC alloantigens are therefore similar to multideterminant protein antigens that bear localized immunodominant a.a. sequences that trigger immune responses toward the whole protein molecule [2,[20][21][22]. This suggests that indirect allorecognition is amenable to specific immunointervention possibly through manipulation of such dominant immunogenic epitopes, similar to previous experiments that modified immunodominant determinants of multideterminant protein antigens.…”

“…Additionally, immediate epitope flanking residues, as well as, downstream sequences have been shown to play a crucial role in epitope recognition by responding T cells [42]. Although analysis of T cell responses to nominal protein or transplantation antigens has shown that constraints in antigen processing and presentation usually limit the T cell responses to one or two dominant determinants [1,8], there is also evidence highlighting the hierarchy of the polyclonal nature of the indirect T cell responses, suggesting the participation of multiple T cell determinants [12,13,[20][21][22]36]. We therefore hypothesize that [α 1h l/u ]-RT1.A a allochimeric molecules containing both dominant donor-type immunogenic epitopes and cryptic subdominant self-epitopes together orchestrate peri-operative transplantation tolerance through manipulation of the indirect pathway.…”