The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8 T Cell Fitness and Functionality
Authors: Zhenqing Ye
Bibo Zhu
Zheng Wang
Jeffrey C Rathmell
Tobias Peikert
Min Xiang
Li Jiang
Reshma Taneja
Jie Sun
Benjamin G Vincent
Chaofan Li
Kathryn E Beckermann
Brian T Edelson
Yue Wu
Taro Hitosugi
Peter J Siska
Y S Prakash
Haidong Dong
James W Jenkins
Mark H Kaplan
Young Min Son
Journal: Immunity (2019)
Discipline: IMMUNOLOGY
Keywords: Bhlhe40; PD-L1; Tubastatin A; acetate; epigenetic
Affiliations: Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA., Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA., Internal Medicine III, University Hospital Regensburg, 93042 Regensburg, Germany; Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA., Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA., Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Department of Physiology, National University of Singapore, Singapore 117593, Singapore., Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: .

Abstract:  Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function. 

Retracted: No

PubPeer comments:
 erratum: (Immunity 51, 491u2013507.e1u2013e7; September 17, 2019) The authors became aware of errors of mislabeling in some panels of this study. In Figure 2F, the schematic summarizing the experimental protocol should have identified PR8-OT-I as PR8-OVA. Meanwhile, in Figure 2G, the identities of the open square and closed square tracings were inadvertently reversed. Finally, the color coding of experimental samples in Figure 6H and the right-hand tracing in Figure 7I were incorrectly assigned. The errors were generated inadvertently during the revision process of the manuscript. This has been corrected online, and the authors sincerely apologize for these errors as well as any confusion this may have caused. u00a9 2019 Elsevier Inc. ,