Ablation of Survivin in T Cells Attenuates Acute Allograft Rejection after Murine Heterotopic Heart Transplantation by Inducing Apoptosis

Abstract

Although studies in oncology have well explored the pharmacological effects of <i>Birc5</i>, little is known about its role in allogeneic T-cell responses. Therefore, the present study used a mouse model of acute heart allograft rejection to investigate the protective effect and mechanism of conditional knockout of <i>Birc5</i> in T cells. Survivin (encoded by <i>Birc5</i>) was up-regulated in T cells activated <i>in vivo</i> and <i>in vitro</i>. Deletion of <i>Birc5</i> in T cells attenuated acute heart allograft rejection by reducing the ratio of effector to naive T cells and Th1 to Tregs. In addition, deletion of <i>Birc5</i> had no noticeable effect on proliferation but on apoptosis and the secretion of IFN-γ. The results revealed a significant increase in the percentage of Annexin V positive CD4⁺ T cells in the <i>Birc5^-/-</i> group, compared to the WT. Moreover, there was significant increase in early apoptotic alloreactive T cells in <i>Birc5</i>^-/- mice and this was partly mediated by caspase-3. Furthermore, treatment with YM155 inhibited acute heart allograft rejection <i>in vivo</i> and increased T-cell apoptosis in healthy human PBMCs <i>in vitro</i>. The results highlight a potential therapeutic target for the prevention and treatment of acute transplant rejection.