mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2090-2108
Number of pages19
JournalJournal of Clinical Investigation
Volume125
Issue number5
DOIs
StatePublished - May 1 2015

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pollizzi, K. N., Patel, C. H., Sun, I. H., Oh, M. H., Waickman, A. T., Wen, J., Delgoffe, G. M., & Powell, J. D. (2015). mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. Journal of Clinical Investigation, 125(5), 2090-2108. https://doi.org/10.1172/JCI77746