title: Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta.
abstract: Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-beta, may play a role in down-regulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4+ T cells were exposed ex vivo to alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-beta. Primary but not secondary alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of IL-10 + TGF-beta markedly induced alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact. In adoptive transfer experiments, IL-10 + TGF-beta-treated CD4+ T cells, but not T cells treated with either cytokine alone, were markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-beta have at least an additive effect in inducing alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4+ T cell-mediated Ag-specific responses in vivo.
authors.affiliation: Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis 55455, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Zeller
authors.forename: A
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: W J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: F W
authors.initials: FW
authors.lastname: Ruscetti
authors.forename: S
authors.initials: S
authors.lastname: Narula
authors.forename: M G
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000401:mortality; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000941:Antigens; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D007519:Isoantigens; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D010047:Ovalbumin