期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 5, 页码 2090-2108出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI77746
关键词
-
资金
- NIH [AI072677, AI77610, AI091481]
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.
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