title: CD28 co-stimulation regulates the effect of transforming growth factor-beta1 on the proliferation of naïve CD4+ T cells.
abstract: Transforming growth factor-beta1 (TGF-beta1) is a critical regulator of T cell responses in vivo. In vitro, TGF-beta1 can either enhance or inhibit T cell proliferative responses, but the relevant factors that determine the T cell response to TGF-beta1 remain obscure. Here, we present evidence that CD28 co-stimulation modifies the effects of TGF-beta1 on T cell proliferation. In the absence of CD28 co-stimulation, TGF-beta1 potently suppressed TCR-stimulated proliferation of naïve T cells. In the presence of CD28 co-stimulation, TGF-beta1 potently inhibited T cell apoptosis and enhanced TCR-stimulated proliferation. A similar effect of CD28 co-stimulation was not observed in memory/effector cells, whose proliferation was enhanced by TGF-beta1, whether co-stimulated or not. We examined the mechanism by which CD28 modulates naïve T cell responses to TGF-beta1. Since CD28 co-stimulation classically is a potent enhancer of interleukin (IL)-2 production, we anticipated observing high IL-2 production from naïve T cells stimulated with anti-CD3/anti-CD28 and TGF-beta1. Surprisingly, however, TGF-beta1 strongly inhibited production of IL-2 from naïve CD4(+) T cells, even when CD28 was engaged. Even though IL-2 levels were strongly suppressed by TGF-beta1 to trace levels, antibody neutralization studies showed that IL-2 is still a basic requirement for the proliferation of anti-CD3/anti-CD28/TGF-beta1-stimulated naïve T cells. These data show that CD28's modulation of T cell responses to TGF-beta1 is not via the production of high levels of IL-2, and suggest that engagement of CD28 may activate additional downstream pathways that modulate the responses of naïve T cells to TGF-beta1.
authors.affiliation: Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Sung
authors.forename: Jack T
authors.initials: JT
authors.lastname: Lin
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004247:DNA / Q000032:analysis; D007376:Interleukin-2 / Q000096:biosynthesis; D016906:Interleukin-9 / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D016906:Interleukin-9; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA