Enhancing CD8 T-cell memory by modulating fatty acid metabolism

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Abstract
CD8 T cells play a crucial role in immunity to infection and cancer. The predictable pattern of a CD8 T-cell response to infection is well established, but the underlying cellular mechanisms regulating the transition to memory remain undefined. Here, Pearce et al. show that metabolic conversion to catabolic pathways of energy generation is key to CD8 T-cell memory development in vivo. CD8 T cells switch from glucose metabolism to fatty acid metabolism as they differentiate into a 'memory' cell that can 'remember' past infections. The process is regulated by the tumour necrosis factor receptor-associated factor protein TRAF6. On antigen stimulation, CD8 T cells undergo a developmental program characterized by expansion and then contraction of antigen-specific effector (TE) populations, followed by the persistence of long-lived memory (TM) cells. During this transition, CD8 T cells are now shown to switch from glucose metabolism to fatty acid metabolism by a TRAF6-dependent mechanism. 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 (TE) populations, followed by the persistence of long-lived memory (TM) cells1,2. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to TM cells remain undefined1,2. 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 TM-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 TE-cell responses, but have a profound defect in their ability to generate TM 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 TM-cell generation in the absence of TRAF6. This treatment also increased CD8 TM cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.