TCF-1 controls T(reg) functions that regulate inflammation, CD8 T-cell cytotoxicity, and severity of colon cancer.

The transcription factor TCF-1 is essential for the development and function of T regulatory (T(reg)) cells, however its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-seq analysis identified effector- and central-memory T(reg)-cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core T(reg) transcriptional signature, but promoted alternative signaling pathways whereby T(reg)-cells became activated and gained gut-homing and T(H)17 characteristics. TCF-1-deficient T(reg)-cells strongly suppressed T-cell proliferation and cytotoxicity, but were compromised in controlling CD4(+) T-cell polarization and inflammation. In mice with polyposis, T(reg) cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating T(reg) cells of colorectal cancer patients showed lower TCF-1 expression and increased T(H)17 expression signatures compared to adjacent normal tissue and circulating T-cells. Thus, T(reg) cell-specific TCF-1 expression differentially regulates T(H)17-mediated inflammation and T-cell cytotoxicity, and can determine colorectal cancer outcome.