CD28 co-stimulation regulates the effect of transforming growth factor-beta1 on the proliferation of naïve CD4+ T cells

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.