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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 Article has an altmetric score of 18

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

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Figure 10

mTORC2 inhibition promotes memory generation.

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mTORC2 inhibition promotes memory generation.
(A–E) 1.5 × 105 naive sort...
(A–E) 1.5 × 105 naive sorted OT-I+ T cells were transferred into WT CD90.2+ recipients infected with vaccinia-OVA. (A and B) Mice were given secondary infection of lm-OVA 133 days after initial infection, and 7 days later, the percentage and absolute number of recovered OT-I+ splenocytes was determined (n = 20). (C) Experimental schematic for D. (D) Flow cytometric analysis of the percentage of OT-I+ cells recovered from blood 35 days after primary infection, with statistics shown on the right (n = 9) (top). OT-I+ cells were purified after harvest on day 35, transferred into new recipients infected with vaccinia-OVA, and 6 days later, percentage of OT-I+ PBMCs was determined (labeled as “D6 after 2nd AT”), with statistics shown to the right (n = 7) (bottom). (E) CD62L and CD127 expression of recovered OT-I+ splenocytes 35 days after primary infection (n = 9). (F) p-FOXO1 protein expression was detected from in vitro–stimulated and IL-7– and IL-15–expanded CD8+ T cells with or without restimulation. 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 < 0.01, ***P < 0.001, Mann-Whitney t tests.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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