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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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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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