Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Zheng Fu, Jian Ye, Joseph W. Dean, John W. Bostick, Samuel E. Weinberg, Lifeng Xiong, Kristen N. Oliff, Zongming E. Chen, Dorina Avram, Navdeep Chandel, Liang Zhou*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity. Cellular metabolism is important for regulatory T cell (Treg) homeostasis and function. Fu et al. show that mitochondrial transcription factor A (Tfam)-mediated mitochondrial respiration is critical for Treg maintenance in non-lymphoid organs and tissues in the steady state and in tumors.

Original languageEnglish (US)
Pages (from-to)159-171.e4
JournalCell reports
Volume28
Issue number1
DOIs
StatePublished - Jul 2 2019

Fingerprint

T-cells
Regulatory T-Lymphocytes
Tumors
Respiration
Maintenance
Tissue
Metabolism
Neoplasms
Homeostasis
DNA Packaging
Inflammation
Methylation
DNA Methylation
Colitis
Transcription
Ablation
DNA Replication
Mitochondrial DNA
Transcriptional Activation
Immunity

Keywords

  • Tfam
  • maintenance
  • mitochondrial respiration
  • regulatory T cells
  • tumor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Fu, Z., Ye, J., Dean, J. W., Bostick, J. W., Weinberg, S. E., Xiong, L., ... Zhou, L. (2019). Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function. Cell reports, 28(1), 159-171.e4. https://doi.org/10.1016/j.celrep.2019.06.024
Fu, Zheng ; Ye, Jian ; Dean, Joseph W. ; Bostick, John W. ; Weinberg, Samuel E. ; Xiong, Lifeng ; Oliff, Kristen N. ; Chen, Zongming E. ; Avram, Dorina ; Chandel, Navdeep ; Zhou, Liang. / Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function. In: Cell reports. 2019 ; Vol. 28, No. 1. pp. 159-171.e4.
@article{787e198610a44975b42b7b9a368e1c34,
title = "Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function",
abstract = "Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity. Cellular metabolism is important for regulatory T cell (Treg) homeostasis and function. Fu et al. show that mitochondrial transcription factor A (Tfam)-mediated mitochondrial respiration is critical for Treg maintenance in non-lymphoid organs and tissues in the steady state and in tumors.",
keywords = "Tfam, maintenance, mitochondrial respiration, regulatory T cells, tumor",
author = "Zheng Fu and Jian Ye and Dean, {Joseph W.} and Bostick, {John W.} and Weinberg, {Samuel E.} and Lifeng Xiong and Oliff, {Kristen N.} and Chen, {Zongming E.} and Dorina Avram and Navdeep Chandel and Liang Zhou",
year = "2019",
month = "7",
day = "2",
doi = "10.1016/j.celrep.2019.06.024",
language = "English (US)",
volume = "28",
pages = "159--171.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",

}

Fu, Z, Ye, J, Dean, JW, Bostick, JW, Weinberg, SE, Xiong, L, Oliff, KN, Chen, ZE, Avram, D, Chandel, N & Zhou, L 2019, 'Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function', Cell reports, vol. 28, no. 1, pp. 159-171.e4. https://doi.org/10.1016/j.celrep.2019.06.024

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function. / Fu, Zheng; Ye, Jian; Dean, Joseph W.; Bostick, John W.; Weinberg, Samuel E.; Xiong, Lifeng; Oliff, Kristen N.; Chen, Zongming E.; Avram, Dorina; Chandel, Navdeep; Zhou, Liang.

In: Cell reports, Vol. 28, No. 1, 02.07.2019, p. 159-171.e4.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

AU - Fu, Zheng

AU - Ye, Jian

AU - Dean, Joseph W.

AU - Bostick, John W.

AU - Weinberg, Samuel E.

AU - Xiong, Lifeng

AU - Oliff, Kristen N.

AU - Chen, Zongming E.

AU - Avram, Dorina

AU - Chandel, Navdeep

AU - Zhou, Liang

PY - 2019/7/2

Y1 - 2019/7/2

N2 - Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity. Cellular metabolism is important for regulatory T cell (Treg) homeostasis and function. Fu et al. show that mitochondrial transcription factor A (Tfam)-mediated mitochondrial respiration is critical for Treg maintenance in non-lymphoid organs and tissues in the steady state and in tumors.

AB - Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity. Cellular metabolism is important for regulatory T cell (Treg) homeostasis and function. Fu et al. show that mitochondrial transcription factor A (Tfam)-mediated mitochondrial respiration is critical for Treg maintenance in non-lymphoid organs and tissues in the steady state and in tumors.

KW - Tfam

KW - maintenance

KW - mitochondrial respiration

KW - regulatory T cells

KW - tumor

UR - http://www.scopus.com/inward/record.url?scp=85067643164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067643164&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.06.024

DO - 10.1016/j.celrep.2019.06.024

M3 - Article

VL - 28

SP - 159-171.e4

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 1

ER -