title: Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cells.
abstract: TGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1.
authors.affiliation: Center for Rheumatology Research, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Brynja
authors.initials: B
authors.lastname: Gunnlaugsdottir
authors.forename: Solrun M
authors.initials: SM
authors.lastname: Maggadottir
authors.forename: Björn R
authors.initials: BR
authors.lastname: Ludviksson
mesh_terms: D018106:CD28 Antigens / Q000276:immunology* / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D009336:Necrosis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1