Murine CTLA4/Fc therapy leads to permanent engraftment of islet allografts in interleukin 4 (IL-4) knockout (IL-4-/- mice. Interestingly, IL-4+/- hosts were more resistant to tolerance induction than IL-4-/- mice. An IL-2/Fc fusion protein abrogates the effect of CTLA4/Fc therapy while an IL-4/Fc fusion protein tends to inhibit rather than enhance the effect of CTLA/Fc treatment in IL-4-/- recipients. We conclude that allograft acceptance requires principally a blockade of T cell activation rather than 'immune deviation' of the T cell activation program to Th2 cytokines (i.e. IL-4).