OKT3 therapy for the treatment of organ graft rejection is complicated by severe first dose side effects caused by T cell activation-induced cytokine release in vivo. Moreover, OKT3 causes pan-immunosuppression that can lead to increased infections and cancer. The investigators have developed a novel Fc receptor (FcR) non-binding form of anti-murine CD3 mAb, 2C11-IgG3, which suppresses immune responses in the absence of first dose side effects. In vitro, 2C11-IgG3 has short-lived effects on naive T cells, but delivers a partial signal to activated T cells that results in clonal inactivation of Th1 cells, proliferation/ cytokine production by Th2 cells, and Th2 deviation of undifferentiated T cells. Biochemical analyses of the early activation events in both T cell subsets show an identical pattern of partial phosphorylation of T cell receptor (TCR) zeta and ZAP-70 similar to that observed in T cells treated with altered CD4 receptor blockade during T cell activation. These results suggest that this novel TCR antagonist can differentially alter the intracellular signals that regulate Th1 and Th2 development selectively on antigen-experienced T cells. The investigators hypothesize that unbalanced biochemical signaling, exemplified by this mAb, is a common mechanism to regulate T cell differentiation and tolerance induction in vivo. The proposed study will focus on several questions: 1) Do the biochemical and functional changes induced by 2C11-IgG3 in vitro also occur in vivo in the allogeneic islet transplant model? 2) Can the mechanisms that regulate this process be defined? 3) What are the minimal biochemical signaling events required for Th cell differentiation? To answer these questions, we propose the following specific aims: 1) Determine the in vivo effect of 2C11-IgG3 mAb on T cell signaling in the allogeneic islet transplant model. 2) Use biochemical analyses and retroviral gene transfer to define the proximal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3. 3) Use biochemical analyses and retroviral gene transfer to define the distal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3.