Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells

Hu, Zhongliang; Qu, Guojun; Yu, Xiaoyan; Jiang, Haojie; Teng, Xiao-Lu; Ding, Lei; Hu, Qianwen; Guo, Xinwei; Zhou, Yan; Wang, Rui; Li, Huabing; Chen, Lei; Jen, Jin; Su, Bing; Liu, Junling; Zou, Qiang

doi:10.1016/j.cmet.2019.05.016

Cited by 63 publications

(76 citation statements)

References 52 publications

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“…PTEN-deficient Tregs rapidly proliferate in response to IL-2 stimulation alone, with restoration of PTEN expression sufficient to reverse this phenotype. 77 More recently, Zou et al 78 identified the lipid kinase acylglycerol kinase (AGK) as a novel regulator of the PI3K-PTEN axis in CD8 T cells. AGK phosphorylates monoacyl glycerol and DAG to generate lysophosphatidic acid and phosphatidic acid, respectively.…”

Section: Bottom-up Metabolic Signalingmentioning

confidence: 99%

Metabolic signaling in T cells

2020

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The maintenance of organismal homeostasis requires partitioning and transport of biochemical molecules between organ systems, their composite cells, and subcellular organelles. Although transcriptional programming undeniably defines the functional state of cells and tissues, underlying biochemical networks are intricately intertwined with transcriptional, translational, and post-translational regulation. Studies of the metabolic regulation of immunity have elegantly illustrated this phenomenon. The cells of the immune system interface with a diverse set of environmental conditions. Circulating immune cells perfuse peripheral organs in the blood and lymph, patrolling for pathogen invasion. Resident immune cells remain in tissues and play more newly appreciated roles in tissue homeostasis and immunity. Each of these cell populations interacts with unique and dynamic tissue environments, which vary greatly in biochemical composition. Furthermore, the effector response of immune cells to a diverse set of activating cues requires unique cellular adaptations to supply the requisite biochemical landscape. In this review, we examine the role of spatial partitioning of metabolic processes in immune function. We focus on studies of lymphocyte metabolism, with reference to the greater immunometabolism literature when appropriate to illustrate this concept.

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Section: Bottom-up Metabolic Signalingmentioning

confidence: 99%

Metabolic signaling in T cells

2020

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“…8 PTEN is repressed upon strong TCR stimulation or CD28 co-stimulation, in part, due to the Tec family kinase IL-2-inducible T cell kinase (Itk), [8][9][10][11] and is also negatively regulated by acylglycerol kinase (AGK)-mediated phosphorylation during CD8 + T cell activation. 12 Mice with T cell-specific PTEN deficiency develop spontaneous autoimmunity associated with hyperactivation of T cells as noted above, as well as lymphoma. 13 Regulatory T (Treg) cell-specific PTEN deficiency also results in autoimmunity due to destabilized Foxp3 expression (also called instability) and diminished suppressive function of Treg cells.…”

Section: Pi3kmentioning

confidence: 91%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

151

136

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Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

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“…18 In addition to those canonical components of mTOR signaling, acylglycerol kinase also maintains the metabolic state and immune responses of CD8 + T cells through positive regulation of PI3K-mTOR signaling, thus highlighting the importance of this pathway in the CD8 + T-cell response. 223 A long-lasting question in the memory T-cell field is how to improve memory-cell formation, because this process is the goal of vaccination and directly relates to the efficacy of immunotherapy.…”

Section: Mtor Signaling In Cd8mentioning

confidence: 99%

“…In support of this idea, genetic deletion of TSC1 leads to a failure to maintain quiescence and is associated with a semi‐activated state of CD8 + T cells in vivo . 18 In addition to those canonical components of mTOR signaling, acylglycerol kinase also maintains the metabolic state and immune responses of CD8 + T cells through positive regulation of PI3K‐mTOR signaling, thus highlighting the importance of this pathway in the CD8 + T‐cell response 223 …”

Section: Physiological Functions Of Mtor In T Cellsmentioning

confidence: 99%

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

Huang

Long

Zhou

et al. 2020

Immunological Reviews

127

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The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T‐cell development, homeostasis, activation, and effector‐cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T‐cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T‐cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.

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Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells

Cited by 63 publications

References 52 publications

Metabolic signaling in T cells

Metabolic signaling in T cells

Signaling networks in immunometabolism

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

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