title: 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.
abstract: 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 Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 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 Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a 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 Ld 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-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.
authors.affiliation: Department of Surgery, University of California at San Francisco 94143-0508, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Fedoseyeva
authors.forename: R C
authors.initials: RC
authors.lastname: Tam
authors.forename: P L
authors.initials: PL
authors.lastname: Orr
authors.forename: M R
authors.initials: MR
authors.lastname: Garovoy
authors.forename: G
authors.initials: G
authors.lastname: Benichou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001685:Biological Factors / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D001324:Autoantigens; D001685:Biological Factors; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010446:Peptide Fragments