TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases
Bi-Huei Yang,
Ke Wang,
Shuo Wan,
Yan Liang,
Xiaomei Yuan,
Yi Dong,
Sunglim Cho,
Wanqing Xu,
Kristen Jepsen,
Gen-Sheng Feng,
Li-Fan Lu,
Hai-Hui Xue,
Wenxian Fu
Affiliations
Bi-Huei Yang
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Ke Wang
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Shuo Wan
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Yan Liang
Department of Pathology, University of California, San Diego, La Jolla, CA, USA; PhD Program, Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Xiaomei Yuan
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Yi Dong
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Sunglim Cho
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Wanqing Xu
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
Kristen Jepsen
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
Gen-Sheng Feng
Department of Pathology, University of California, San Diego, La Jolla, CA, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
Li-Fan Lu
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
Hai-Hui Xue
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Iowa City Veterans Affairs Health Care System, Iowa City, IA 52246, USA; Corresponding author
Wenxian Fu
Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Corresponding author
Summary: CD4+ Foxp3+ T regulatory (Treg) cells are key players in preventing lethal autoimmunity. Tregs undertake differentiation processes and acquire diverse functional properties. However, how Treg’s differentiation and functional specification are regulated remains incompletely understood. Here, we report that gradient expression of TCF1 and LEF1 distinguishes Tregs into three distinct subpopulations, particularly highlighting a subset of activated Treg (aTreg) cells. Treg-specific ablation of TCF1 and LEF1 renders the mice susceptible to systemic autoimmunity. TCF1 and LEF1 are dispensable for Treg’s suppressive capacity but essential for maintaining a normal aTreg pool and promoting Treg’s competitive survival. As a consequence, the development of T follicular regulatory (Tfr) cells, which are a subset of aTreg, is 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 autoimmunity. : Transcriptional regulation of Treg differentiation and function remains incompletely understood. Yang et al. report that two TCF family transcription factors regulate the survival and functional specification of a subset of Treg cells to prevent autoimmunity. Keywords: regulatory T cells, TCF1, LEF1, autoimmunity, Tfr, homeostasis, competitive fitness
