Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention.

Tissue-resident memory T (Trm) cells represent a population of memory CD8⁺ T cells that can act as first responders to local infection. The mechanisms regulating the formation and maintenance of intestinal Trm cells remain elusive. Here we showed that transforming growth factor-β (TGF-β) controlled both stages of gut Trm cell differentiation through different mechanisms. During the formation phase of Trm cells, TGF-β signaling inhibited the migration of effector CD8⁺ T cells from the spleen to the gut by dampening the expression of integrin α4β7. During the maintenance phase, TGF-β was required for the retention of intestinal Trm cells at least in part through the induction of integrins αEβ7 and α1, as well as CD69. Thus, the cytokine acts to control cytotoxic T cell differentiation in lymphoid and peripheral organs.