1. Department of Pathology and Laboratory Medicine,
2. Department of Microbiology,
3. Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
4. McGill Cancer Centre, Department of Physiology, McGill University, Montreal, QC, H3G 1Y6, Canada

Correspondence to: Yongwon Choi¹ Correspondence and requests for materials should be addressed to Y.C. (Email: ychoi3@mail.med.upenn.edu).

CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T_E) populations, followed by the persistence of long-lived memory (T_M) cells^{1, 2}. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T_M cells remain undefined^{1, 2}. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T_M-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T_E-cell responses, but have a profound defect in their ability to generate T_M cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T_M-cell generation in the absence of TRAF6. This treatment also increased CD8 T_M cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.

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