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

mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation

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

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Figure 11

mTORC2 inhibition leads to enhanced metabolic fitness.

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mTORC2 inhibition leads to enhanced metabolic fitness. Purified CD8+ T c...
Purified CD8+ T cells from WT or T-Rictor–/– mice were stimulated in vitro for 48 hours and expanded for 3 days. (A) Initial ECAR, initial OCR, and (B) SRC were determined. Data are mean ± SEM of 7 measurements. (C) WT, T-Rheb–/–, and T-Rictor–/– CD8+ T cells were stimulated in vitro and cultured in IL-7 and IL-15 for 3 days. Cells were plated at equivalent cell number, and ECAR and OCR measurements were assayed upon stimulation in the Seahorse bioanalyzer. Data are mean ± SEM of 12 measurements. (D) SRC was determined after restimulation of WT, T-Rheb–/–, and T-Rictor–/– CD8+ T cells expanded in IL-7 and IL-15. Data are mean ± SEM of 10 measurements. Relative expression of Cpt1a transcript was determined from (E) stimulated cells expanded in IL-7 and IL-15 for 3 days (mean ± SEM of 3 measurements) or from (F) sorted WT, T-Rheb–/–, and T-Rictor–/– OT-I+ cells recovered 6 days after adoptive transfer into recipients infected with vaccinia-OVA (n = 3 mice per genotype). (G) OCR measurements of restimulated WT, T-Rheb–/–, and T-Rictor–/–CD8+ T cells during a FAO assay. BSA control shown in gray. Data are mean ± SEM of 4 measurements. Statistics in A, B, D, and F were determined by ANOVA; those in C were measured by repeated-measures analysis; and those in E were measured by Mann-Whitney t test. Data are representative of at least 3 independent experiments. For the box-and-whiskers plots, the whiskers represent the minimum and maximum values, the box boundaries represent the 25th and 75th percentiles, and the middle line is the median value. *P < 0.05, **P < 0.01, ***P < 0.001.