Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCR? Repertoire.

ABSTRACT: CD8?? TCR??+ 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?? 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?? precursors and limits their private TCR? repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCR??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?? cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8?? cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15-driven maturation of CD8?? 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?? precursors and their TCR? repertoire, but not in the maintenance of CD8?? intraepithelial lymphocytes in the intestine.

SUBMITTER: Li KP 

PROVIDER: S-EPMC5568849 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature