mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation

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Abstract

Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4⁺ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8⁺ T cell effector and memory populations. Evaluation of mice with a T cell–specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8⁺ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8⁺ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8⁺ T cell effector responses, mTORC2 activity regulated CD8⁺ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8⁺ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8⁺ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.

Authors

Kristen N. Pollizzi, Chirag H. Patel, Im-Hong Sun, Min-Hee Oh, Adam T. Waickman, Jiayu Wen, Greg M. Delgoffe, Jonathan D. Powell