Metabolism and CD8+ T cell immunity
Rao, Rajesh R.
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Metabolism comprises anabolic and catabolic processes that produce and degrade macromolecules in an energy dependent manner. The balance in metabolic activity is essential for physiological homeostasis, and the imbalance in metabolism such as overfeeding-induced obesity, has been increasingly associated with chronic disease states such as type II diabetes and cardiovascular diseases. Emerging evidence indicates that metabolic imbalance also affects host immunity, as infections and incidence of malignancies are increased in obese people. Since, the CD8 + T cells are a major component of the host immune response that controls intracellular infections and tumors; it is not surprising that the host metabolic status is a critical regulator of CD8 + T cell proliferation, survival and functional differentiation. The characterization of the mechanisms by which host metabolic status regulates CD8 + T cell response would provide useful insights to overcome the challenge of increased infections and cancers under conditions of metabolic imbalance such as obesity, diabetes and/or ageing. The prevailing concepts have attributed the need for metabolic energy for proliferation and cell survival of T cells. However, a possible role for the metabolic pathways in regulating gene programs that imprint functional differentiation of CD8 + T cells is not well characterized. By serendipity, we observed that proinflammatory cytokine interleukin-12 (IL-12), that programs antigen activated CD8 + T cells for type I effector maturation, also enhances and sustains the activity of energy sensitive kinase mTOR complex 1 (mTORC1). The increase in IL-12 induced mTORC1 activity is required for mTORC2 dependent inactivation of transcription factor FoxO1, which is essential for increase in master transcription factor T-bet and type I effector differentiation of CD8 + T cells. Conversely, blocking mTORC1 activity by rapamycin reversed IL-12 enhanced T-bet expression and promoted persistent expression of memory associated transcription factor-Eomesodermin in a FoxO1 dependent manner. Rapamycin treated IL-12 conditioned OT-I cells demonstrated enhanced memory responses and greater tumor efficacy than IL-12 conditioned effector OT-I cells upon adoptive transfer. Further, in delineating a molecular basis for impaired CD8 + T cell responses in diet-induced obese mice (DIO), we found dampened mTORC1 expression in CD8 + T cells from DIO mice, which was due to a decrease in AMPK-SIRT1 activity; pathways upstream of mTOR acting as primordial sensors of energy availability. Strikingly, the defects in mTORC1 pathway were restored by caloric restriction mimics like Resveratrol (activators of AMPK-SIRT1 pathway), which enhanced mTORC1 activity and restored T-bet dependent effector functions in CD8 + T cells from DIO mice. Collectively, these results identify mTOR as the central regulator of CD8 + T cell differentiation program and establish a novel role for metabolic pathways in regulating gene programs that imprint functional differentiation of CD8 + T cells. This information has established a new paradigm for CD8 + T cell responses, which can help overcome immune defects associated with metabolic imbalance and offers new opportunities to regulate CD8 + T cell memory responses for durable immunity.