Organ transplantation remains the most important therapeutic option for end-stage organ failure, but success of this procedure is limited by the eventual rejection of almost all grafts. T cells reject grafts by recognizing genetic differences between recipient and donor. Activation of T cells by donor antigens drives clonal expansion of graft-reactive T cells. The magnitude of the response depends on a balance between T cell activation and death. Understanding the mechanisms that regulate cell death may result in new approaches to prevent graft failure. I found that human CD8 T cells activated in the presence of IL-1, IL-6, and IL-23 were protected against activation-induced cell death (AICD) as a result of increases in c-FLIPS expression induced by IL-6. I then used an aortic interposition model of transplant arteriosclerosis (TA), a form of arterial rejection that is the main cause of heart transplant failure, to determine the effect of IL-6 on T cell death. Grafted arteries that lacked IL-6 developed less severe rejection as compared to IL-6+/+ arteries, and this correlated with an increase in T cell death. These findings indicate that IL-6 inhibits T cell death after organ transplantation. I also examined the intrinsic regulation of T cell responses by Bcl-2 family proteins. Bim is a pro-apoptotic protein known to down-regulate immune responses. Besides inducing T cell death, I found that Bim was unexpectedly required for proliferation of T cells in response to alloantigen stimulation in vitro. A partial reduction in Bim expression was sufficient to attenuate activation whereas a complete elimination of Bim was required to prevent CD4 T cell death in response to cytokine withdrawal. In vivo, there was significantly less vascular rejection in Bim+/-, but not Bim-/-, graft recipients. T cell proliferation in response to allograft arteries was significantly reduced in both Bim+/- and Bim-/- mice, but cell death was attenuated only in Bim-/- animals. These findings indicate that Bim regulates not only T cell death but also allogeneic T cell activation. In summary, my work has provided insight into the mechanisms by which extrinsic and intrinsic regulators of cell death affect immune responses in transplantation. These pathways are potential targets in the development of novel therapies to manage TA.
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Thesis advisor: Choy, Jonathan
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