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

Abu Osman, Bingyu Yan, Ying Li, Kevin D. Pavelko, Jasmine Quandt, Abdulrahman Saadalla, Mahendra Pal Singh, Majid Kazemian, Fotini Gounari, Khashayarsha Khazaie

Research output: Contribution to journalArticlepeer-review

Abstract

The transcription factor TCF-1 is essential for the development and function of regulatory T (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-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. 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 patients with colorectal cancer 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.

Original languageEnglish (US)
Pages (from-to)1152-1162
Number of pages11
JournalNature immunology
Volume22
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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