Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire

CD8 alpha alpha TCR alpha beta(+) intestinal intraepithelial lymphocytes play a critical role in promoting intestinal homeostasis, although mechanisms controlling their development and peripheral homeostasis remain unclear. In this study, we examined the spatiotemporal role of Bim in the thymic selection of CD8 alpha alpha precursors and the fate of these cells in the periphery. We found that T cell-specific expression of Bim during early/cortical, but not late/medullary, thymic development controls the agonist selection of CD8 alpha alpha precursors and limits their private TCR beta repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCR alpha beta(hi) thymocytes. Although these DN thymocytes fail to re-express coreceptors after OP9-DL1 culture, they eventually mature and accumulate in the spleen where TCR and IL-15/STAT5 signaling promotes their conversion to CD8 alpha alpha cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8 alpha alpha cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15-driven maturation of CD8 alpha alpha cells that is critical for intestinal homeostasis. Thus, we found a temporal and tissue-specific role for Bim in limiting thymic agonist selection of CD8 alpha alpha precursors and their TCR beta repertoire, but not in the maintenance of CD8 alpha alpha intraepithelial lymphocytes in the intestine.