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 S. Chandel,
Liang Zhou
Affiliations
Zheng Fu
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Jian Ye
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Joseph W. Dean
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
John W. Bostick
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA
Samuel E. Weinberg
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Lifeng Xiong
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Kristen N. Oliff
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Zongming E. Chen
Geisinger Medical Center, Laboratory Medicine, 01-31, 100 North Academy Avenue, Danville, PA 17822, USA
Dorina Avram
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32608, USA
Navdeep S. Chandel
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Liang Zhou
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA; Corresponding author
Summary: 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: regulatory T cells, mitochondrial respiration, Tfam, maintenance, tumor
