@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 Chandel, {Navdeep S.} and Liang Zhou",
note = "Funding Information: We thank all L.Z. lab members for help and suggestions. We thank the Genomics Facility (University of Chicago) for sequencing services and assistance. We thank Dr. L. Yang at the University of California, Los Angeles for providing the B16-OVA tumor cell line. We thank Dr. T. Tran and Dr. M. Kong at the University of California, Irvine for technical support for anti-5-meC dot blotting. This work was made possible in part by NIH Instrumentation Grant 1S10 OD021676-01 . L.Z. is a Pew Scholar in Biomedical Sciences, supported by the Pew Charitable Trusts , and an Investigator in the Pathogenesis of Infectious Disease, supported by the Burroughs Wellcome Fund . The work was supported by the NIH ( AI132391 and DK105562 to L.Z.). Funding Information: We thank all L.Z. lab members for help and suggestions. We thank the Genomics Facility (University of Chicago) for sequencing services and assistance. We thank Dr. L. Yang at the University of California, Los Angeles for providing the B16-OVA tumor cell line. We thank Dr. T. Tran and Dr. M. Kong at the University of California, Irvine for technical support for anti-5-meC dot blotting. This work was made possible in part by NIH Instrumentation Grant 1S10 OD021676-01. L.Z. is a Pew Scholar in Biomedical Sciences, supported by the Pew Charitable Trusts, and an Investigator in the Pathogenesis of Infectious Disease, supported by the Burroughs Wellcome Fund. The work was supported by the NIH (AI132391 and DK105562 to L.Z.). Z.F. and J.Y. designed the experiments. Z.F. J.Y. and S.E.W. performed the experiments. Z.F. J.Y. J.W.B. J.W.D. L.X. and Z.E.C. analyzed the data. D.A. and N.S.C. provided reagents and advice. L.Z. supervised the study. Z.F. and L.Z. wrote the manuscript with input from the other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jul,
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",
}