Abstract
Abstract CD4+Foxp3+T regulatory (Treg) cells are key players in preventing lethal autoimmunity and deleterious tissue inflammation. To fulfill this role, Treg cells undertake activation and differentiation processes and acquire diverse functional properties. However, how Treg’s differentiation and functional specifications are regulated remains incompletely understood. Here we show that gradient expression of two TCF/LEF family transcription factors, TCF1 and LEF1, distinguishes Treg cells into three distinct populations. Treg-specific ablation of TCF1 and LEF1 renders the mice susceptible to tissue immunopathology and aberrant activation of cellular and humoral responses. TCF1 and LEF1 are essential for promoting Treg’s competitive survival. In addition, the development of T follicular regulatory (Tfr) cells is completely abolished in TCF1/LEF1-conditional knockout mice, leading to unrestrained T follicular helper (Tfh) and germinal center B cell responses. Thus, TCF1 and LEF1 act redundantly to control the maintenance and functional specification of Treg subsets to prevent autoimmune and inflammatory diseases.
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