Mitochondrial Perturbations Couple mTORC2 to Autophagy in &lt;i&gt;C. elegans&lt;/i&gt;

Aspernig, Helena; Qi, Wenjing; Yan, Yizhen; Gromoff, Erika Donner von; Baumeister, Ralf; Thien, Antje

doi:10.2139/ssrn.3353705

Cited by 1 publication

(1 citation statement)

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“…These data suggest that mTORC2 is necessary to activate the immune response of CD8+ T cells ( Figures 4F,G ), a fact that has already been reported in vitro ( 56 ). Evidence for a link between ROS and mTORC2 was reported using C. elegans , in which it was observed that mTORC2 activity reduces ROS generation, enhancing cell surviving ( 57 ). Similarly, inhibition of mTORC2 in human cancerous cells increases damage produced by ROS ( 58 ).…”

Section: Resultsmentioning

confidence: 99%

Metabolic alterations impair differentiation and effector functions of CD8+ T cells

2022

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CD8+ T lymphocytes are one of the main effector cells of the immune system, they protect the organism against intracellular threats such as viruses and bacteria, as well as neoplasms. It is currently well established that CD8+ T cells have distinct immune responses, given by their phenotypes Tc1, Tc2, Tc17, and TcReg. The cellular plasticity of such phenotypes depends on the presence of different combinations of cytokines in the extracellular medium. It is known that metabolic imbalances play an important role in immune response, but the precise role of metabolic disturbances on the differentiation and function of CD8+ T cells, however, has not been explored. In this work, we used a computational model to explore the potential effect of metabolic alterations such as hyperglycemia, high alcohol consumption, dyslipidemia, and diabetes on CD8+ T cell differentiation. Our model predicts that metabolic alterations preclude the effector function of all CD8+ T cell phenotypes except for TcReg cells. It also suggests that such inhibition originates from the increase of reactive oxygen species in response to metabolic stressors. Finally, we simulated the outcome of treating metabolic-inhibited CD8+ T cells with drugs targeting key molecules such as mTORC1, mTORC2, Akt, and others. We found that overstimulation of mTORC2 may restore cell differentiation and functions of all effector phenotypes, even in diabetic patients. These findings highlight the importance of our predictive model to find potential targets to strengthen immunosuppressed patients in chronic diseases, like diabetes.

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Section: Resultsmentioning

confidence: 99%