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

doi:10.1016/j.celrep.2019.05.061

TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases

Cell Rep. 2019 Jun 18;27(12):3629-3645.e6. doi: 10.1016/j.celrep.2019.05.061.

Authors

Bi-Huei Yang¹, Ke Wang¹, Shuo Wan², Yan Liang³, Xiaomei Yuan¹, Yi Dong¹, Sunglim Cho⁴, Wanqing Xu¹, Kristen Jepsen⁵, Gen-Sheng Feng⁶, Li-Fan Lu⁷, Hai-Hui Xue⁸, Wenxian Fu⁹

Affiliations

¹ Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
² 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.
³ 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.
⁴ Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
⁵ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.
⁶ 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.
⁷ 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.
⁸ 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. Electronic address: hai-hui-xue@uiowa.edu.
⁹ 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. Electronic address: w3fu@ucsd.edu.

Abstract

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.

Keywords: LEF1; TCF1; Tfr; autoimmunity; competitive fitness; homeostasis; regulatory T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Autoimmune Diseases / immunology
Autoimmune Diseases / pathology
Autoimmune Diseases / prevention & control*
Autoimmunity / immunology*
Cell Differentiation
Female
Germinal Center / immunology*
Hepatocyte Nuclear Factor 1-alpha / physiology*
Lymphoid Enhancer-Binding Factor 1 / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Regulatory / immunology*

Substances

Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Lef1 protein, mouse
Lymphoid Enhancer-Binding Factor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding