T-bet deficiency and Hic1 induction override TGF-β-dependency in the formation of CD103⁺ intestine-resident memory CD8⁺ T cells

Transforming growth factor β (TGF-β) represents a well-established signal required for tissue-resident memory T cell (T_RM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal T_RM differentiation. The functional contribution from each TGF-β-controlled transcription factor is not entirely known. Here, we find that TGF-β-induced T-bet downregulation and Hic1 induction represent two critical events during intestinal T_RM differentiation. Importantly, T-bet deficiency significantly rescues intestinal T_RM formation in the absence of the TGF-β receptor. Hic1 induction further strengthens T_RM maturation in the absence of TGF-β and T-bet. Our results reveal that provision of certain TGF-β-induced molecular events can partially replace TGF-β signaling to promote the establishment of intestinal T_RMs, which allows the functional dissection of TGF-β-induced transcriptional targets and molecular mechanisms for T_RM differentiation.