title: Costimulation through OX40 is crucial for induction of an alloreactive human T-cell response.
abstract: The alloreactive immune response is a series of events initiated by the interaction of T cells with allogeneic dendritic cells (DCs), involving alloantigen recognition and costimulatory signals. In this study, we investigated the role of OX40 in alloreactivity in vitro. We first demonstrated that anti-OX40 ligand (anti-OX40L) monoclonal antibody (mAb) could markedly suppress the mixed leucocyte reaction (MLR) of peripheral blood mononuclear cells (PBMC). To further define the contribution of the OX40/OX40L system to the MLR, we set up a co-culture system of CD4+ T cells and allogeneic monocyte-derived dendritic cells (DCs). After 2 days, OX40 expression was induced on CD4+ T cells and this induction was strongly inhibited by the addition of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Fc fusion protein, suggesting that the expression of OX40 during alloreaction is dependent on CD28 signalling. Next we examined the effects of anti-OX40L mAb, CTLA-4-Fc fusion protein and anti-human leucocyte antigen (HLA)-DR mAb on the proliferative response of CD4+ T cells to allogeneic DCs. The proliferation of T cells was almost completely suppressed by anti-OX40L mAb, which was comparable with that of CTLA-4-Fc. Measurement of interleukin-2 (IL-2) production in the culture supernatants showed that suppression of a proliferative response was at least in part ascribed to reduced IL-2 production. Furthermore, purified OX40L- allogeneic DCs could induce considerable proliferation of CD4+ T cells, which was suppressed by anti-OX40L mAb. These results suggest that the OX40/OX40L system is crucial for induction of the allogeneic T-cell response and the OX40/OX40L system is subsequent to and dependent on CD28 signalling, but is crucial for the end outcome of the human alloreactive T-cell response.
authors.affiliation: Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ukyo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hori
authors.forename: Soshi
authors.initials: S
authors.lastname: Yanagita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uchiyama
mesh_terms: D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D053278:OX40 Ligand; D011971:Receptors, Immunologic / Q000276:immunology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D007519:Isoantigens; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D011971:Receptors, Immunologic; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000069594:Abatacept