| First Author | Reina-Campos M | Year | 2023 |
| Journal | Nature | Volume | 621 |
| Issue | 7977 | Pages | 179-187 |
| PubMed ID | 37648857 | Mgi Jnum | J:371215 |
| Mgi Id | MGI:7647056 | Doi | 10.1038/s41586-023-06483-w |
| Citation | Reina-Campos M, et al. (2023) Metabolic programs of T cell tissue residency empower tumour immunity. Nature 621(7977):179-187 |
| abstractText | 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. |
