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Metabolic programs of T cell tissue residency empower tumour immunity
Open accessAbstract
Tissue resident memory CD8+ T (T RM) cells offer rapid and long-term protection at sites of reinfection 1. Tumour-infiltrating lymphocytes with characteristics of T RM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses 2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting T RM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where T RM cells interface with dietary cholesterol and maintain a heightened state of activation 4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of T RM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
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“Cholesterol homeostasis has also been implicated in tissue resident memory CD8 T cells (70).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [70]
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Self-citation
Metadata
- Authors
- Reina-Campos, M., Heeg, M., Kennewick, K., Mathews, I. T., Galletti, G., Luna, V., Nguyen, Q., Huang, H., Milner, J. J., Hu, K. H., Vichaidit, A., Santillano, N., Boland, B. S., Chang, J. T., Jain, M., Sharma, S., Krummel, M. F., Chi, H., Bensinger, S. J., & Goldrath, A. W.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- La Jolla Institute for Immunology (US)
- St. Jude Children's Research Hospital (US)
- University of North Carolina at Chapel Hill (US)
- University of California, San Francisco (US)
- Corresponding author
- Goldrath, Ananda W.
- ORCID
- Venue
- Nature
- Published
- 2023-08-30
- Volume
- 621
- Issue
- 7977
- Pages
- 179-187
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11238873
- OpenAlex
- W4386304015
- Cited by
- 132
- References
- 69
- Citations by year
- 2026: 32 · 2025: 54 · 2024: 41 · 2023: 5
- FWCI
- 14.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute (GT14887)
- Cancer Research Institute (CRI4145)
- Leona M. and Harry B. Helmsley Charitable Trust
- National Institutes of Health (1s10od021815-01, 1s10od026929-01, P30 014195, CA030199, DK063720, AI132122, HL146358, AI067545)
- University of California, San Diego (#S10 OD026929)
- University of California, San Francisco (P30DK063720, DK063720)
- National Heart, Lung, and Blood Institute (P01HL146358, R01HL157710)
- National Cancer Institute (P30014195, CA 030199, 1S10OD021815, R01CA256133, P30CA030199, P30CA014195, P50CA257911, R01CA197363)
- National Institute of Allergy and Infectious Diseases (R01AI067545, R01AI150282, R01AI072117, P01AI132122, R37AI067545, R37AI052116)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063720)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- tissue-resident memory T cells, tumor-infiltrating lymphocytes, coenzyme Q biosynthesis, SREBP2, FDFT1, PDSS2, mitochondrial respiration, antitumor immunity, memory T cell differentiation, viral infection, small intestine, immunotherapy
- MeSH terms
- Animals, Cholesterol, Humans, Immunologic Memory, Intestine, Small, Mevalonic Acid, Mitochondria, Neoplasms, Ubiquinone, Virus Diseases, Viruses, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Cell Respiration, Alkyl and Aryl Transferases, Mice, Sterol Regulatory Element Binding Protein 2, Metabolomics
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