The in vivo administration of the immunosuppressive drug, Cyclosporin A (CSA), has allowed us to define IL-2 dependent and IL-2 independent pathways of T cell activation in vivo. Thus, CSA inhibited T cell activation and the production of IL-2 mRNA in the draining lymph node (LN) population following footpad injection of anti-CD3 mAb. In contrast, even though CSA completely inhibited the induction of IL-2 mRNA in the draining LN following the injection of allogeneic cells, T cell activation proceeded normally. In the present study, we have analyzed the effects of CSA on the T cell activation induced in vivo by T. cruzi. BALB/c and C57BL/6 mice were injected subcutaneously in the footpad with irradiated, cultured T. cruzi trypomastigotes (CMTs, clone sylvio-X10/4). CSA was delivered to the mice via an osmotic pump, Alzet 2001 at a concentration of 35mg/Kg/day. The injection of CMTs resulted in a dose dependent activation of the draining LN population including an increase in the number of cells, an increase in cell size, induction of expression of the IL-2 receptor and other T cell activation antigens (Ly-6, CD28), induction of responsiveness to IL-2, and a vigorous proliferative response when the freshly explanted node was cultured for 18 h in vitro in the presence of 3H-TdR. CSA markedly inhibited all of these parameters of T cell activation. Thus, the early T cell activation response observed after injection of irradiated T. cruzi CMTs appears to be mediated by an IL-2 dependent, CSA sensitive T cell activation pathway.