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 (TRM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal TRM 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 TRM differentiation. Importantly, T-bet deficiency significantly rescues intestinal TRM formation in the absence of the TGF-β receptor. Hic1 induction further strengthens TRM 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 TRMs, which allows the functional dissection of TGF-β-induced transcriptional targets and molecular mechanisms for TRM differentiation. [Display omitted] •T-bet deficiency partially rescues TGF-βR-KO TRM formation in the small intestine•T-bet-deficiency-induced type 17 program inhibits gut TRM formation•Hic1 further boosts gut TRM differentiation in the absence of TGF-β receptor Wang et al. find that T-bet deficiency significantly rescues intestine TRM differentiation in TGF-βR-KO cells. Suppressing the type 17 program or enforced expression of Hic1 further boosts TRM formation in T-bet/TGF-βR DKO T cells. These results show the key molecular events downstream of TGF-β signaling during intestine TRM differentiation.