T FH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function

Fengyin Li; Xin Zhao; Yali Zhang; Peng Shao; Xiaoke Ma; William J Paradee; Chengyu Liu; Jianmin Wang; Hai-Hui Xue

doi:10.1073/pnas.2014562118

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T FH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function

Journal article

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Peer reviewed

T FH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function

Fengyin Li, Xin Zhao, Yali Zhang, Peng Shao, Xiaoke Ma, William J Paradee, Chengyu Liu, Jianmin Wang and Hai-Hui Xue

Proceedings of the National Academy of Sciences - PNAS, Vol.118(2), 2014562118

01/12/2021

DOI: 10.1073/pnas.2014562118

PMCID: PMC7812797

PMID: 33372138

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Abstract

Precise regulation of coinhibitory receptors is essential for maintaining immune tolerance without interfering with protective immunity, yet the mechanism underlying such a balanced act remains poorly understood. In response to protein immunization, T follicular helper (T ) cells lacking Tcf1 and Lef1 transcription factors were phenotypically normal but failed to promote germinal center formation and antibody production. Transcriptomic profiling revealed that Tcf1/Lef1-deficient T cells aberrantly up-regulated CTLA4 and LAG3 expression, and treatment with anti-CTLA4 alone or combined with anti-LAG3 substantially rectified B-cell help defects by Tcf1/Lef1-deficient T cells. Mechanistically, Tcf1 and Lef1 restrain chromatin accessibility at the and loci. Groucho/Tle corepressors, which are known to cooperate with Tcf/Lef factors, were essential for T cell expansion but dispensable for repressing coinhibitory receptors. In contrast, mutating key amino acids in histone deacetylase (HDAC) domain in Tcf1 resulted in CTLA4 derepression in T cells. These findings demonstrate that Tcf1-instrinsic HDAC activity is necessary for preventing excessive CTLA4 induction in protein immunization-elicited T cells and hence guarding their B-cell help function.

Animals

Antigens, CD

B-Lymphocytes - metabolism

CD8-Positive T-Lymphocytes - immunology

Cell Differentiation - immunology

CTLA-4 Antigen - metabolism

Female

Germinal Center - immunology

Hepatocyte Nuclear Factor 1-alpha - immunology

Hepatocyte Nuclear Factor 1-alpha - metabolism

Immune Tolerance

Lymphoid Enhancer-Binding Factor 1 - immunology

Lymphoid Enhancer-Binding Factor 1 - metabolism

Male

Mice

Mice, Inbred C57BL

Proto-Oncogene Proteins c-bcl-6

T Follicular Helper Cells - immunology

T Follicular Helper Cells - metabolism

T-Lymphocytes, Helper-Inducer - immunology

Details

Title: Subtitle: T FH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function
Creators: Fengyin Li - University of Science and Technology of China
Xin Zhao - Center for Discovery
Yali Zhang - Roswell Park Comprehensive Cancer Center
Peng Shao - University of Iowa
Xiaoke Ma - Xidian University
William J Paradee - University of Iowa
Chengyu Liu - National Heart Lung and Blood Institute
Jianmin Wang - Roswell Park Comprehensive Cancer Center
Hai-Hui Xue - Hackensack University Medical Center
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.118(2), 2014562118
DOI: 10.1073/pnas.2014562118
PMID: 33372138
PMCID: PMC7812797
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: R01 AI112579 / NIAID NIH HHS R01 AI121080 / NIAID NIH HHS I01 BX002903 / BLRD VA R01 AI139874 / NIAID NIH HHS P30 CA016056 / NCI NIH HHS
Language: English
Date published: 01/12/2021
Academic Unit: Microbiology and Immunology; Medicine Administration
Record Identifier: 9984622754302771

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