Kazemian, Majid

Abstract The transcription factor TCF-1 is essential for the development and function of T regulatory (Treg) 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 Treg-cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg transcriptional signature, but promoted alternative signaling pathways whereby Treg-cells became activated and gained gut-homing and TH17 characteristics. TCF-1-deficient Treg-cells strongly suppressed T-cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T-cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of colorectal cancer patients showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T-cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T-cell cytotoxicity, and can determine colorectal cancer outcome. Supported by NIH R01 AI 108682 (FG & KK), NIH RO1 AI 147652 (FG), NIH R35GM138283 (MK), and Praespero Innovation Award Alberta, Canada (FG & KK)

Abstract TCF1 is essential for the development and function of T regulatory cells (Tregs). However, how TCF1 regulates Treg function in homeostasis or under pathogenic conditions is poorly understood. Here, we ablated TCF1 in Tregs to elucidate its role in Treg specification in healthy mice and mice with colon cancer. RNAseq revealed that TCF1-deficient Tregs maintain their core transcriptional signature, but promote T-cell receptor, Tgfβ receptor, TH17, and Wnt/β-catenin signaling pathways. Single-cell RNAseq identified central-memory-Tregs with low Klf2 or high Mif expression, which upon downregulation of TCF1 gained TH17 characteristics and matured into Maf expressing effector Tregs. Tcf1-deficient Tregs exhibited enhanced suppression of T-cell proliferation and cytotoxicity but were compromised in controlling CD4+ T-cell polarization and inflammation. In mice with polyposis, Tcf1-deficient Tregs promoted inflammation and tumor growth. Thus, TCF1 differentially regulates Treg control of TH17 inflammation and T-cell cytotoxicity, and its action in Tregs determines colorectal cancer outcome.