STAT4 increases the phenotypic and functional heterogeneity of intestinal tissue-resident memory T cells.

Tissue-resident memory T cells (Trms) are an important subset of lymphocytes that are lodged within non-lymphoid tissues and carry out diverse functions to control local pathogen replication. CD103 has been used to broadly define subsets of Trms within the intestine, with CD103 and CD103 subsets having unique transcriptional profiles and effector functions. Here we identify signal transducer and activator of transcription 4 (STAT4) as an important regulator of CD103 Trm differentiation. STAT4-deficient cells trafficked to the intestine and localized to areas of infection but displayed impaired Trm differentiation with fewer CD103 Trms. Single-cell RNA-sequencing demonstrated that STAT4-deficiency led to a reduction in CD103 Trm subsets and expansion of a single population of CD103 cells. Alterations in Trm populations were due, in part, to STAT4-mediated inhibition of transforming growth factor (TGF)-β-driven expression of Trm signature genes. STAT4-dependent Trm populations expressed genes associated with cytokine production and cell migration, and STAT4-deficient Trm cells had altered localization within the tissue and reduced effector function after reactivation in vivo. Overall, our data indicate that STAT4 leads to increased differentiation of CD103 Trms, in part by modulating the expression of TGF-β-regulated genes, and results in increased Trm heterogeneity and function within the intestinal tissue.