CD28 co-stimulation regulates the effect of transforming growth factor- beta 1 on the proliferation of naive CD4 super(+) T cells

Transforming growth factor- beta 1 (TGF- beta 1) is a critical regulator of T cell responses in vivo. In vitro, TGF- beta 1 can either enhance or inhibit T cell proliferative responses, but the relevant factors that determine the T cell response to TGF- beta 1 remain obscure. Here, we present evidence that CD28 co- stimulation modifies the effects of TGF- beta 1 on T cell proliferation. In the absence of CD28 co-stimulation, TGF- beta 1 potently suppressed TCR-stimulated proliferation of naive T cells. In the presence of CD28 co-stimulation, TGF- beta 1 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- beta 1, whether co-stimulated or not. We examined the mechanism by which CD28 modulates naive T cell responses to TGF- beta 1. Since CD28 co-stimulation classically is a potent enhancer of interleukin (IL)-2 production, we anticipated observing high IL-2 production from naive T cells stimulated with anti-CD3/anti-CD28 and TGF- beta 1. Surprisingly, however, TGF- beta 1 strongly inhibited production of IL- 2 from naive CD4 super(+) T cells, even when CD28 was engaged. Even though IL-2 levels were strongly suppressed by TGF- beta 1 to trace levels, antibody neutralization studies showed that IL-2 is still a basic requirement for the proliferation of anti-CD3/anti-CD28/TGF- beta 1-stimulated naive T cells. These data show that CD28's modulation of T cell responses to TGF- beta 1 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 naive T cells to TGF- beta 1.