Modulation of T Cell Metabolism and Function through Calcium Signaling

Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.

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Metabolic and functional impairment of CD8+ T cells from the lungs of influenza-infected obese mice

10.1101/2020.04.19.047282 ◽

2020 ◽

Author(s):

William D. Green ◽

Abrar E. Al-Shaer ◽

Qing Shi ◽

Nancie J MacIver ◽

Melinda A. Beck ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Post Infection ◽

Cytokine Production ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Obese Mice ◽

Diet Induced Obesity ◽

And Function

ABSTRACTBackgroundObesity increases influenza disease risk in millions of adults worldwide. In this study, we investigated the effect of diet-induced obesity on pulmonary CD8+ T cell metabolism and function as a mechanism of impairment.MethodsMale C57BL/6J mice were fed either control (10% kcal/g) or high-fat (60% kcal/g) diet. Sub-lethal A/PR/8/34 influenza virus infection generated a robust pulmonary immune response. T cell metabolism and function were assessed at day 10 and day 24 post infection.ResultsAt day 10 post infection, CD8+ T cells from obese mice had impaired oxidative and glycolytic metabolism, greater fatty acid uptake, and decreased effector populations and cytokine production. At infection resolution, obese mice had lower numbers of naïve and central memory CD8+ T cell populations in the lungs.ConclusionDiet-induced obesity increases influenza virus pathogenesis through CD8+ T cell mediated metabolic reprogramming resulting in suppressed effector CD8+ T cell function.SummaryDiet-induced obesity impairs the metabolism of pulmonary CD8+ T cells resulting in reduced effector CD8+ T cells and cytokine production following primary influenza infection.

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Hypoxia-inducible factors regulate T cell metabolism and function

Molecular Immunology ◽

10.1016/j.molimm.2015.08.004 ◽

2015 ◽

Vol 68 (2) ◽

pp. 527-535 ◽

Cited By ~ 33

Author(s):

Anthony T. Phan ◽

Ananda W. Goldrath

Keyword(s):

T Cell ◽

Cell Metabolism ◽

Hypoxia Inducible Factors ◽

And Function

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The Regulatory Effects of mTOR Complexes in the Differentiation and Function of CD4+ T Cell Subsets

Journal of Immunology Research ◽

10.1155/2020/3406032 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Peng Wang ◽

Qian Zhang ◽

Liang Tan ◽

Yanan Xu ◽

Xubiao Xie ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Metabolism ◽

Adaptive Immune System ◽

Treg Cells ◽

T Cell Subsets ◽

Regulatory Effects ◽

Phosphoinositide 3 Kinase ◽

T Cell Subpopulations ◽

And Function

T cells are an important part of the adaptive immune system and play critical roles in the elimination of various pathogens. T cells could differentiate into distinct cellular subsets under different extracellular signals and then play different roles in maintaining host homeostasis and defense. The mechanistic target of rapamycin (mTOR) is a conserved intracellular serine/threonine kinase which belongs to the phosphoinositide 3-kinase- (PI3K-) related kinase family. The mTOR signaling pathway is closely involved in a variety of cell biological processes, including cell growth and cell metabolism, by senses and integrates various environmental cues. Recent studies showed that mTOR including mTORC1 and mTORC2 is closely involved in the development of T cell subpopulations such as Th1, Th2, Th9, Th17, follicular helper T cells (Tfh), and Treg cells through distinctive pathways. We herein mainly focused on the recent progress in understanding the roles of mTOR in regulating the development and differentiation of CD4+ T cell subsets.

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Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease

Current Opinion in Immunology ◽

10.1016/j.coi.2017.04.006 ◽

2017 ◽

Vol 46 ◽

pp. 82-88 ◽

Cited By ~ 44

Author(s):

Chirag H Patel ◽

Jonathan D Powell

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Metabolism ◽

And Function

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Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome

Journal of Experimental Medicine ◽

10.1084/jem.20180397 ◽

2018 ◽

Vol 215 (9) ◽

pp. 2463-2476 ◽

Cited By ~ 16

Author(s):

Xiaoyan Yu ◽

Xiao-Lu Teng ◽

Feixiang Wang ◽

Yuhan Zheng ◽

Guojun Qu ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Cell Metabolism ◽

Signaling Mechanism ◽

Cell Responses ◽

Mtorc1 Signaling ◽

Cell Stability ◽

Underlying Mechanisms ◽

And Function ◽

Metabolic Fitness

Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg–specific deletion of Traf3ip3 impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)–mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.

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The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy

eLife ◽

10.7554/elife.55185 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 13

Author(s):

Aaron R Lim ◽

W Kimryn Rathmell ◽

Jeffrey C Rathmell

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Cell Metabolism ◽

Tumor Infiltrating Lymphocytes ◽

T Cell Signaling ◽

Waste Products ◽

Cancer Cell Metabolism ◽

And Function ◽

Infiltrating Lymphocytes

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

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