mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
Kristen N. Pollizzi, … , Greg M. Delgoffe, Jonathan D. Powell
Kristen N. Pollizzi, … , Greg M. Delgoffe, Jonathan D. Powell
Published April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2090-2108. https://doi.org/10.1172/JCI77746.
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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 4

The ability of hyperactive mTORC1 signaling to promote effector function is cell intrinsic.

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The ability of hyperactive mTORC1 signaling to promote effector function...
(A) OT-I+CD90.1+CD8+ T cells from WT, T-Rheb–/–, and T-Tsc2–/– mice were adoptively transferred into WT CD90.2+ recipient mice infected with vaccinia-OVA. Six days after infection, splenocytes were harvested. The percentage of splenic CD8+ CD90.1+ T cells, KLRG1 expression of CD8+CD90.1+ cells, and IFN-γ and TNF-α production after SIINFEKL peptide stimulation are shown, with statistics to the right (n = 10). 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. (B) WT and T-Tsc2–/– mice received s.q. EL4 thymoma cells expressing luciferase. Tumor burden was assessed by detection of luminescence (n = 16). (C–E) In vitro–activated T-Rheb–/– and T-Tsc2–/– and littermate control OT-I+CD8+ T cells were injected into WT recipients that had received B16-OVA cells 6 days prior (dashed line represents T cell transfer). “No transfer” indicates that mice did not receive OT-I+ cells. (C) Tumor volume was assessed every 2 to 3 days. Each symbol represents an average per genotype (n = 15). (D) Tumor volume shown at day 24 after tumor inoculation. Each dot represents a mouse. Data are derived from C. (E) Survival was assessed. Mice that received T-Tsc2–/– cells had enhanced survival compared with all other treatments, as determined by multiple comparisons Mantel-Cox tests. Statistics in A and D were determined by ANOVA and for B and C were determined by repeated-measures analysis. Data are representative of at least 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001