BATF regulates progenitor to cytolytic effector CD8 + T cell transition during chronic viral infection

Yao Chen; Ryan A Zander; Xiaopeng Wu; David M Schauder; Moujtaba Y Kasmani; Jian Shen; Shikan Zheng; Robert Burns; Elizabeth J Taparowsky; Weiguo Cui

doi:10.1038/s41590-021-00965-7

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BATF regulates progenitor to cytolytic effector CD8 + T cell transition during chronic viral infection

Journal article

Peer reviewed

BATF regulates progenitor to cytolytic effector CD8 + T cell transition during chronic viral infection

Yao Chen, Ryan A Zander, Xiaopeng Wu, David M Schauder, Moujtaba Y Kasmani, Jian Shen, Shikan Zheng, Robert Burns, Elizabeth J Taparowsky and Weiguo Cui

Nature immunology, Vol.22(8), pp.996-1007

08/2021

DOI: 10.1038/s41590-021-00965-7

PMCID: PMC9258987

PMID: 34282329

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https://www.ncbi.nlm.nih.gov/pmc/articles/9258987View

Open Access

Abstract

During chronic viral infection, CD8 T cells develop into three major phenotypically and functionally distinct subsets: Ly108 TCF-1 progenitors, Ly108 CX CR1 terminally exhausted cells and the recently identified CX CR1 cytotoxic effector cells. Nevertheless, how CX CR1 effector cell differentiation is transcriptionally and epigenetically regulated remains elusive. Here, we identify distinct gene regulatory networks and epigenetic landscapes underpinning the formation of these subsets. Notably, our data demonstrate that CX CR1 effector cells bear a striking similarity to short-lived effector cells during acute infection. Genetic deletion of Tbx21 significantly diminished formation of the CX CR1 subset. Importantly, we further identify a previously unappreciated role for the transcription factor BATF in maintaining a permissive chromatin structure that allows the transition from TCF-1 progenitors to CX CR1 effector cells. BATF directly bound to regulatory regions near Tbx21 and Klf2, modulating their enhancer accessibility to facilitate the transition. These mechanistic insights can potentially be harnessed to overcome T cell exhaustion during chronic infection and cancer.

Animals

Antigens, Ly - metabolism

Basic-Leucine Zipper Transcription Factors - metabolism

CD8-Positive T-Lymphocytes - cytology

CD8-Positive T-Lymphocytes - immunology

Cell Differentiation - genetics

Cell Differentiation - immunology

Cell Line

CX3C Chemokine Receptor 1 - metabolism

Female

Hepatocyte Nuclear Factor 1-alpha - metabolism

Kruppel-Like Transcription Factors - genetics

Lymphocytic Choriomeningitis - immunology

Lymphocytic choriomeningitis virus - immunology

Male

Mice

Mice, Inbred C57BL

Mice, Knockout

T-Box Domain Proteins - genetics

T-Lymphocyte Subsets - cytology

T-Lymphocyte Subsets - immunology

Details

Title: Subtitle: BATF regulates progenitor to cytolytic effector CD8 + T cell transition during chronic viral infection
Creators: Yao Chen - Medical College of Wisconsin
Ryan A Zander - Versiti Blood Center of Wisconsin
Xiaopeng Wu - Versiti Blood Center of Wisconsin
David M Schauder - Medical College of Wisconsin
Moujtaba Y Kasmani - Medical College of Wisconsin
Jian Shen - Medical College of Wisconsin
Shikan Zheng - Versiti Blood Center of Wisconsin
Robert Burns - Versiti Blood Center of Wisconsin
Elizabeth J Taparowsky - Purdue University West Lafayette
Weiguo Cui - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: Nature immunology, Vol.22(8), pp.996-1007
DOI: 10.1038/s41590-021-00965-7
PMID: 34282329
PMCID: PMC9258987
NLM abbreviation: Nat Immunol
ISSN: 1529-2908
eISSN: 1529-2916
Grant note: R01 AI148403 / NIAID NIH HHS F30 DK108557 / NIDDK NIH HHS F30 CA246920 / NCI NIH HHS R01 AI125741 / NIAID NIH HHS T32 GM080202 / NIGMS NIH HHS
Language: English
Date published: 08/2021
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297438002771

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