Metabolic programs of T cell tissue residency empower tumour immunity

Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T. Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J. Justin Milner, Kenneth H. Hu, Amy Vichaidit, Natalie Santillano, Brigid S. Boland, John T. Chang, Mohit Jain, Sonia Sharma, Matthew F. Krummel, Hongbo Chi, Steven J. Bensinger and Ananda W. Goldrath ()
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Miguel Reina-Campos: University of California, San Diego
Maximilian Heeg: University of California, San Diego
Kelly Kennewick: David Geffen School of Medicine at UCLA
Ian T. Mathews: La Jolla Institute for Immunology
Giovanni Galletti: University of California, San Diego
Vida Luna: University of California, San Diego
Quynhanh Nguyen: University of California, San Diego
Hongling Huang: St. Jude Children’s Research Hospital
J. Justin Milner: University of North Carolina at Chapel Hill School of Medicine
Kenneth H. Hu: University of California, San Francisco
Amy Vichaidit: David Geffen School of Medicine at UCLA
Natalie Santillano: David Geffen School of Medicine at UCLA
Brigid S. Boland: University of California, San Diego
John T. Chang: University of California, San Diego
Mohit Jain: University of California, San Diego
Sonia Sharma: La Jolla Institute for Immunology
Matthew F. Krummel: University of California, San Francisco
Hongbo Chi: St. Jude Children’s Research Hospital
Steven J. Bensinger: David Geffen School of Medicine at UCLA
Ananda W. Goldrath: University of California, San Diego

Nature, 2023, vol. 621, issue 7977, 179-187

Abstract: Abstract Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. 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 TRM 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 TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, 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 TRM 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.

Date: 2023
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DOI: 10.1038/s41586-023-06483-w

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