Bim regulates allogeneic immune responses and transplant arteriosclerosis through opposing effects on T cell activation and death. (P2218)

Abstract

Abstract T cell responses towards allograft arteries are responsible for the development of transplant arteriosclerosis (TA), a vascular condition characterized by intimal thickening of graft arteries. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses by inducing effector T cell death, but its role in regulating allogeneic T cell responses is poorly understood. We compared allo-activation and death of T cells from Bim+/+, Bim+/- and Bim-/- mice as well as the development of TA in these animals. Unexpectedly, Bim was required for alloantigen-induced proliferation of both CD4 and CD8 T cells, as well as IL-2 production. Partial reduction in Bim expression was sufficient to attenuate T cell activation while complete elimination was required to prevent T cell death driven by cytokine deprivation in vitro. When TA was examined in aortic interposition grafts, intimal thickening was significantly reduced in Bim+/- but not Bim-/- recipients. There was significantly less CD4 T cell accumulation in the intima of arteries from Bim+/- as compared to Bim+/+ recipients, but this effect was not observed in Bim-/- mice. Further, T cell proliferation was significantly reduced in both Bim+/- and Bim-/- mice in response to allograft arteries but T cell death was attenuated only in Bim-/- animals. Taken together, our findings show that Bim controls both T cell activation and death in TA, and that these processes are differentially susceptible to reductions in Bim expression.