title: Antigenic strength controls the generation of antigen-specific IL-10-secreting T regulatory cells.
abstract: Administration of peptides i.n. induces peripheral tolerance in Tg4 myelin basic protein-specific TCR-Tg mice. This is characterized by the generation of anergic, IL-10-secreting CD4+ T cells with regulatory function (IL-10 Treg). Myelin basic protein Ac1-9 peptide analogs, displaying a hierarchy of affinities for H-2 A(u) (Ac1-9[4K]<<[4A]<[4Y]), were used to investigate the mechanisms of tolerance induction, focusing on IL-10 Treg generation. Repeated i.n. administration of the highest affinity peptide, Ac1-9[4Y], provided complete protection against EAE, while i.n. Ac1-9[4A] and Ac1-9[4K] treatment resulted in only partial protection. Ac1-9[4Y] was also the most potent stimulus for IL-10 Treg generation. Although i.n. treatment with Ac1-9[4A] gave rise to IL-10-secreting CD4+ T cells, the population as a whole was also capable of secreting IFN-gamma after an in vitro recall response to Ac1-9[4A] or [4Y]. In addition to IL-10 production, other facets of tolerance, namely, anergy and suppression (both in vitro and in vivo), were affinity dependent, with i.n. Ac1-9[4Y]-, [4A]- or [4K]-treated CD4+ T cells being the most, intermediate and least anergic/suppressive, respectively. These findings demonstrate that the generation of IL-10 Treg in vivo is driven by high signal strength.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol School of Medical Sciences, Bristol, UK.
authors.forename: Leona
authors.initials: L
authors.lastname: Gabrysová
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D007376:Interleukin-2; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016753:Interleukin-10; D007371:Interferon-gamma