Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Ikeda, Kayo; Kinoshita, Makoto; Kayama, Hisako; Nagamori, Shushi; Kongpracha, Pornparn; Umemoto, Eiji; Okumura, Ryu; Kurakawa, Takashi; Murakami, Masuo; Mikami, Norihisa; Shintani, Yasunori; Ueno, Satoko; Andou, Ayatoshi; Ito, Morihiro; Tsumura, Hideki; Yasutomo, Koji; Ozono, Keiichi; Takashima, Seiji; Sakaguchi, Shimon; Kanai, Yoshikatsu; Takeda, Kohsuke

doi:10.1016/j.celrep.2017.10.082

Cited by 93 publications

(90 citation statements)

References 46 publications

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“…Indeed, the induction of leucine-and glutamine-driven mTORC1 activation is impaired in LAT1-and ASCT2-deficient T cells, respectively, 111,114 and mTORC1 activation is also reduced in CD98-deficient Treg cells, probably due to reduced isoleucine influx. 115 Intriguingly, amino acids are also critical for promoting TCR-and CD28-dependent mTORC1 signaling in Treg cells, 112,116 suggesting that amino acids and, possibly other nutrients, not only promote mTORC1 activation, but are also a prerequisite for immunological receptors to induce (a process we have termed 'licensing' 112 ) and sustain activity of mTORC1. Whether other nutrients also prime immune receptor signaling pathways at the level of mTORC1 or other signaling pathways remains unexplored.…”

Section: Metabolic and Immunological Inputs For Mtorc1mentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

137

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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Section: Metabolic and Immunological Inputs For Mtorc1mentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

137

136

View full text Add to dashboard Cite

show abstract

“…23,52,53,54,55,56 Moreover, the amino acid transporters CD98-LAT1 and ASCT2 are important for driving mTORC1 activation in naive T cells, activated T cells, and Treg cells. [54][55][56][57][58] The asymmetric segregation of amino acid transporters leads to altered mTOR accumulation in the DC-proximal and DC-distal daughter cells during the first division of CD8 + T cells, which ultimately contributes to fate decisions of memory-like and effector-like CD8 + T cells. 59,60 Recently, we have also shown that amino acids can regulate mTORC1 activity in Treg cells by driving dissociation of the TSC complex from the lysosome, which likely allows RHEB to activate mTORC1 in cooperation with the Rag complex.…”

Section: Tcr Co-stimulatory Receptors and Cytokinesmentioning

confidence: 99%

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

Huang

Long

Zhou

et al. 2020

Immunological Reviews

124

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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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“…RA-induced pTreg cell generation underlies oral tolerance, as mice treated with a vitamin A-deficient diet display defective in the induction of oral tolerance (193). Recent studies have also indicated a critical role for isoleucine in regulating Treg cell homeostasis in the small intestine (194). Other dietary mechanisms controlling the homeostasis of small intestinal Treg cells in vivo require further investigation.…”

Section: Intestinementioning

confidence: 99%

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

2019

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Regulatory T (Treg) cells are crucial for peripheral immune tolerance and prevention of autoimmunity and tissue damage. Treg cells are inherently defined by the expression of the transcription factor Foxp3, which enforces lineage development and immune suppressive function of these cells. Under various conditions as observed in autoimmunity, cancer and non-lymphoid tissues, a proportion of Treg cells respond to specific environmental signals and display altered stability, plasticity and tissue-specific heterogeneity, which further shape their context-dependent suppressive functions. Recent studies have revealed that metabolic programs play pivotal roles in controlling these processes in Treg cells, thereby considerably expanding our understanding of Treg cell biology. Here we summarize these recent advances that highlight how cell-extrinsic factors, such as nutrients, vitamins and metabolites, and cell-intrinsic metabolic programs, orchestrate Treg cell stability, plasticity, and tissue-specific heterogeneity. Understanding metabolic regulation of Treg cells should provide new insight into immune homeostasis and disease, with important therapeutic implications for autoimmunity, cancer, and other immune-mediated disorders.

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Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Cited by 93 publications

References 46 publications

Signaling networks in immunometabolism

Signaling networks in immunometabolism

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

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

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