Metabolic programs of T cell tissue residency empower tumour immunity

Tissue resident memory CD8 T (T ) cells offer rapid and long-term protection at sites of reinfection . Tumour-infiltrating lymphocytes with characteristics of T cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses . Thus, an improved understan...

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Bibliographic Details
Published in:Nature (London) 2023-09, Vol.621 (7977), p.179-187
Main Authors: Reina-Campos, Miguel, Heeg, Maximilian, Kennewick, Kelly, Mathews, Ian T, Galletti, Giovanni, Luna, Vida, Nguyen, Quynhanh, Huang, Hongling, Milner, J Justin, Hu, Kenneth H, Vichaidit, Amy, Santillano, Natalie, Boland, Brigid S, Chang, John T, Jain, Mohit, Sharma, Sonia, Krummel, Matthew F, Chi, Hongbo, Bensinger, Steven J, Goldrath, Ananda W
Format: Article
Language:English
Subjects:
Adaptation
Animals
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cell differentiation
Cell Respiration
Cell survival
Cholesterol
Cholesterol - metabolism
Cholesterol - pharmacology
Coenzyme Q
CRISPR
Diet
Differentiation (biology)
Effector cells
Empowerment
Enzymes
Genes
Genomics
Humans
Immunity
Immunologic Memory
Immunological memory
Immunotherapy
Infections
Intestine
Intestine, Small - drug effects
Intestine, Small - metabolism
Lymphocytes
Lymphocytes T
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Memory cells
Metabolism
Metabolites
Metabolomics
Mevalonic Acid - metabolism
Mice
Mitochondria - metabolism
Neoplasms - immunology
Proteins
Small intestine
Solid tumors
Spleen
T cell receptors
Tissues
Transcription factors
Transcriptomics
Tumors
Ubiquinone - metabolism
Viral infections
Virus Diseases - immunology
Viruses
Viruses - immunology
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Summary:Tissue resident memory CD8 T (T ) cells offer rapid and long-term protection at sites of reinfection . Tumour-infiltrating lymphocytes with characteristics of T cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses . 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 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 cells interface with dietary cholesterol and maintain a heightened state of activation , 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 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.
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-023-06483-w