IL-2-independent activation and proliferation in human T cells induced by CD28

Although the role of CD28 in T cell costimulation is firmly established, th e mechanisms by which it exerts its costimulatory actions are less clear. I n many circumstances it is difficult to distinguish the effects of CD28 fro m subsequent actions of cytokines, such as IL-2, on T cell proliferation. H ere, we report a model of CD28 costimulation using PR IA plus the natural l igand CD80 that resulted in very limited stimulation of IL-2, as evidenced by both cytokine production and IL-2 promoter stimulation. Promoter assays revealed CD28-dependent effects on both NF-kappa B and AP-1, but not on NF- AT or the intact IL-2 promoter, In addition, T cell proliferation was compl etely resistant to the actions of the immunosuppressant cyclosporin A (CsA) , Moreover T cell proliferation was unaffected by the addition of blocking Abs to both IL-2 and the IL-2 receptor, demonstrating that this form of cos timulation by CD28 was independent of IL-2. We also investigated the effect s of stimulating T cell blasts with CD80 alone and found that there was a l imited requirement for IL-2 in this system. We conclude that CD28 costimula tion can cause substantial T cell proliferation in the absence of IL-2, whi ch is driven by a soluble factor independent of NF-AT transactivation.