PRESENTATION OF A SELF-PEPTIDE FOR IN-VIVO TOLERANCE INDUCTION OF CD4(+) T-CELLS IS GOVERNED BY A PROCESSING FACTOR THAT MAPS TO THE CLASS-II REGION OF THE MAJOR HISTOCOMPATIBILITY COMPLEX LOCUS

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide L(d) 61-80 was immunogenic in syngeneic B10.A mice CH-2(a). We showed that despite its high affinity for self-MHC class II molecules, L(d) 61-80 peptide failed to induce elimination of autoreactive CD4(+) T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide L(d) 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2(d)) (dominant self-peptide). In addition, the self-peptide L(d) 61-80 was found to be immunogenic in different H-2(a) mice while it was invariably tolerogenic in H-2(d) mice regardless of their background genes. We observed that L(d) 61-80 bound equally well to H-2(d) and H-2(k) MHC class II molecules. Also, no correlation was found between the quantity of self-L(d) protein and the tolerogenicity of L(d) 61-80. Surprisingly, L(d) 61-80 was not naturally presented in (H-2(d) X H-2(a)) F1 mice, indicating that the H-2(a) MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of L(d) 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This Study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4(+) T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2(a) mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide L(d) 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.