The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8 + T Cell Fitness and Functionality.

Autor:	Li C; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Zhu B; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Son YM; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Wang Z; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Jiang L; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Xiang M; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Ye Z; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA., Beckermann KE; Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Wu Y; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA., Jenkins JW; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA., Siska PJ; Internal Medicine III, University Hospital Regensburg, 93042 Regensburg, Germany; Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Vincent BG; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA., Prakash YS; Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA., Peikert T; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA., Edelson BT; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Taneja R; Department of Physiology, National University of Singapore, Singapore 117593, Singapore., Kaplan MH; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Rathmell JC; Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Dong H; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA., Hitosugi T; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., Sun J; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: sun.jie@mayo.edu.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2019 Sep 17; Vol. 51 (3), pp. 491-507.e7.
DOI:	10.1016/j.immuni.2019.08.013
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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