Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells

Shaojun Xing; Kexin Gai; Xiang Li; Peng Shao; Zhouhao Zeng; Xudong Zhao; Xin Zhao; Xia Chen; William J Paradee; David K Meyerholz; Weiqun Peng; Hai-Hui Xue

doi:10.1084/jem.20182010

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Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells

Journal article

Open access

Peer reviewed

Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells

Shaojun Xing, Kexin Gai, Xiang Li, Peng Shao, Zhouhao Zeng, Xudong Zhao, Xin Zhao, Xia Chen, William J Paradee, David K Meyerholz, …

The Journal of experimental medicine, Vol.216(4), pp.847-866

04/01/2019

DOI: 10.1084/jem.20182010

PMCID: PMC6446865

PMID: 30837262

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Abstract

Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg-overrepresented signature genes such as and Unexpectedly, Tcf1 and Lef1 were necessary for restraining expression of cytotoxic CD8 effector T cell-associated genes in T reg cells, including and Tcf1 ChIP-seq revealed substantial overlap between Tcf1 and Foxp3 binding peaks in the T reg cell genome, with Tcf1-Foxp3 cooccupancy observed at key T reg signature and cytotoxic effector genes. Our data collectively indicate that Tcf1 and Lef1 are critical for sustaining T reg suppressive functions and preventing loss of self-tolerance.

Animals

CD8-Positive T-Lymphocytes - metabolism

Cell Differentiation - genetics

Colitis - chemically induced

Colitis - metabolism

Dextran Sulfate - pharmacology

Disease Models, Animal

Female

Hepatocyte Nuclear Factor 1-alpha - genetics

Hepatocyte Nuclear Factor 1-alpha - metabolism

Immune Tolerance

Lymphoid Enhancer-Binding Factor 1 - genetics

Lymphoid Enhancer-Binding Factor 1 - metabolism

Male

Mice

Mice, Inbred C57BL

Mice, Transgenic

T-Lymphocytes, Regulatory - immunology

T-Lymphocytes, Regulatory - metabolism

Transcriptome - immunology

Details

Title: Subtitle: Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells
Creators: Shaojun Xing - Shenzhen University
Kexin Gai - University of Iowa
Xiang Li - George Washington University
Peng Shao - University of Iowa
Zhouhao Zeng - George Washington University
Xudong Zhao - China Medical University (PRC)
Xin Zhao - University of Iowa
Xia Chen - University of Iowa
William J Paradee - University of Iowa
David K Meyerholz - University of Iowa
Weiqun Peng - George Washington University
Hai-Hui Xue - Iowa City Veterans Affairs Health Care System, Iowa City, IA
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.216(4), pp.847-866
DOI: 10.1084/jem.20182010
PMID: 30837262
PMCID: PMC6446865
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: R01 AI112579 / NIAID NIH HHS R01 AI121080 / NIAID NIH HHS I01 BX002903 / BLRD VA S10 OD016199 / NIH HHS R01 AI139874 / NIAID NIH HHS P30 DK054759 / NIDDK NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 04/01/2019
Academic Unit: Microbiology and Immunology; Pathology; Medicine Administration
Record Identifier: 9984186407202771

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