TCF-1 controls Treg cell functions that regulate inflammation, CD8+ T cell cytotoxicity and severity of colon cancer

Khazaie and colleagues show that TCF-1 cooperates with FOXP3 to differentially regulate independent suppressive activities of T-reg cells. T-reg cell-specific deficiency of TCF-1 increases tumor load in mice predisposed to polyposis. Functionally, TCF-1-deficient T-reg cells suppress viral antigen-specific CD8(+) T cell cytotoxicity, but TCF-1-deficient T-reg cells fail to suppress T(H)1 or T(H)17 polarization of conventional CD4(+) T cells. This scenario leads to increased cytokine-mediated tissue inflammation but still restrains the adaptive antitumor cytotoxicity. The transcription factor TCF-1 is essential for the development and function of regulatory T (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-sequencing analysis identified effector memory T cells 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 cell transcriptional signature, but promoted alternative signaling pathways whereby T-reg cells became activated and gained gut-homing properties and characteristics of the T(H)17 subset of helper T cells. 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 patients with colorectal cancer 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.

Automated summary

Research shows that TCF-1 collaborates with FOXP3 to regulate suppressive activities of T-reg cells, with TCF-1 deficiency promoting inflammation and compromising T-cell cytotoxicity control. TCF-1 primarily suppresses transcription of co-bound genes by Foxp3, and deficiency in TCF-1 leads to activation and characteristics of the T(H)17 subset in T-reg cells. TCF-1 deficiency in T-reg cells can determine colorectal cancer outcome by regulating inflammation and T-cell cytotoxicity.