Enhancing CD8 T-cell memory by modulating fatty acid metabolism

Abstract

CD8 T cells, which play a crucial role in immunity to infection and cancer, are maintained in constant numbers, but upon 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 remain undefined1 , 2 . Here we show that TRAF6, an adapter protein in the TNF-receptor (TNFR) and IL-1R/TLR superfamily, regulates CD8 T M development following infection by modulating fatty acid metabolism. We show that mice with a T cell-specific deletion of TRAF6 mount robust CD8 T E responses, but have a profound defect in their ability to generate T M that is characterized by the disappearance of antigen-specific cells in the weeks following 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 AMPK-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 generation in the absence of TRAF6. Remarkably, this treatment also increased CD8 T M in wild type mice, and consequently was able to significantly improve the efficacy of an experimental anti-cancer vaccine.A prevailing paradigm in immunology is that antigenic signal strength drives progressive T cell differentiation 3 . To investigate this model regarding T M , we studied CD8 T cell responses to bacterial infection in mice with a T cell-specific deletion of TRAF6 (TRAF6-ΔT), a negative regulator of antigen-specific T cell activation 4 . Despite having fewer total CD8 T cells (SI Fig. 1), TRAF6-ΔT mice mounted normal Ova-specific T E responses to attenuated L. monocytogenes expressing Ova (LmOva) (Fig. 1a and SI Fig. 2). To examine CD8 T M in TRAF6-ΔT mice, we immunized with LmOva and measured Ova-specific cells 60 days postinfection. Although Ova-specific T E responses were intact, CD8 T M generation in TRAF6-

Does diabetes therapy influence the risk of cancer?

“…A further experiment showed that metformin treatment increased CD8 + T memory cell populations in wild-type mice, and enhanced the efficacy of anti-cancer vaccination. These intriguing findings indicate a shared mitochondrial nexus for metabolic and immune pathways, and imply that metformin may also have a direct influence upon immune competence [14].…”

“…Another interesting mechanism for the anti-oncogenic effect of metformin has been postulated, based on the findings of a study of mice with CD8 + T lymphocytes which lack tumour necrosis factor receptor-associated factor 6 (TRAF6) and are unable to generate T memory cells [14]. This failure was associated with defective fatty acid oxidation.…”

miR-146acontrols the resolution of T cell responses in mice

“…Proper resolution of a T cell response is as essential as its initiation because of the possible severe pathological consequences of a hyperinflammatory response. (King et al, 2006;Maitra et al, 2009;Pearce et al, 2009). For instance, TRAF6 regulates CD4 + T cell suppression by T reg cells through the PI3K (phosphatidylinositol 3-kinase)-Akt pathway (King et al, 2006), and it regulates CD8 + T cell memory development through the fatty acid metabolism pathway (Pearce et al, 2009).…”

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…47 Further, it has been demonstrated that fattyacid metabolism is key to memory T-cell development and survival. 48,49 Thus, it is possible that in addition to directly regulating T-cell retention in tissues, HIC1 may also be required in T cells to promote quiescence through metabolic pathways. Future studies will aim to characterize the role for HIC1 in T-cell quiescence and memory development.…”