Bim expression in early DP thymocytes limits development of TCRαβ+DN thymocytes and CD8αα intestinal intraepithelial lymphocytes (HEM2P.243)

Abstract

Abstract Thymocyte negative selection is thought to cull T cells with strong self-reactivity and maintain T cells with non-self-specificity. While initial work implicated Bim as a critical mediator of thymocyte negative selection, its role in the process has been controversial. Thus, we re-examined thymocyte development in mice with global and T cell specific loss of Bim. We found that global Bim-/- mice had a striking accumulation of DN4 thymocytes expressing high levels of surface TCR, which failed to generate DP cells in OP9-DL1 culture. Interestingly, CD4Cre-driven deletion of Bim promoted DN4 cells, but later, dLckCre-driven deletion of Bim did not. Combined, these data show that the aberrant DN4 cells in Bim-/- mice were once DP cells, but had lost co-receptor expression. Investigating the fate of these cells, we found that splenic DN T and gut CD8αα T cells were increased in Bim-/- mice. While IL-15 is critical for both DN/CD8αα T cells, the additional loss of Bim partially restored DN/CD8αα T cells in IL-15 deficient mice, suggesting that IL-15 signals antagonize Bim to promote DN T and CD8αα T cells. Finally, TCR or IL-15 signals were sufficient to promote expression of both CD8αα and the gut homing receptor CCR9 on splenic DN T cells. In conclusion, these data further delineate the role of Bim on thymocyte fate and DN/CD8αα T cell development; and show that dLckCre-Bimf/f mice can isolate the effects of Bim on peripheral T cell survival without affecting thymic selection.