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 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.