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The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8(+) T cell fitness and functionality
- Source :
- Immunity
- Publication Year :
- 2019
-
Abstract
- Summary 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.
- Subjects :
- 0301 basic medicine
Cell
Immunology
Programmed Cell Death 1 Receptor
chemical and pharmacologic phenomena
Biology
CD8-Positive T-Lymphocytes
Article
Epigenesis, Genetic
03 medical and health sciences
Mice
0302 clinical medicine
Lymphocytes, Tumor-Infiltrating
Immunity
PD-L1
medicine
Basic Helix-Loop-Helix Transcription Factors
Immunology and Allergy
Cytotoxic T cell
Animals
Epigenetics
Gene
Transcription factor
Homeodomain Proteins
Tumor-infiltrating lymphocytes
hemic and immune systems
Cell biology
Mitochondria
Social Control, Formal
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Infectious Diseases
Gene Expression Regulation
030220 oncology & carcinogenesis
biology.protein
Immunologic Memory
CD8
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....37c67d412be27294c012289f1688147c