Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation

By M. Nakaya, Yichuan Xiao, Jae-Hoon Chang, Mikyoung Chang, Xuhong Cheng, M. Blonska, Xin Lin, Shao-Cong Sun. Immunity, 2014

786 citations recorded by the source corpus.

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T-cell activation is poorly understood. We have shown that naïve T-cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper-1 (Th1) and Th17 cells and attenuated inflammatory T-cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T-cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.

Subfields: Biochemistry, Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/b57edbb5206d7084aa26a3bafcd89cd27922e33e

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In Biochemistry

1. Russell G. Jones
2. Erika L. Pearce
3. J. Rathmell

In Cancer Research

1. Michael D. Buck
2. Erika L. Pearce
3. Russell G. Jones
4. J. Rathmell
5. David O’Sullivan

In Immunology

1. Erika L. Pearce
2. Michael D. Buck
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5. J. Rathmell
6. G. V. D. van der Windt
7. C. Piccirillo
8. S. Kaech

Citations in the corpus

• T cell metabolism drives immunity (2015, background): “It was recently found that loss of ASCT2 decreased glutamine import and impaired OXPHOS and glucose metabolism in activated CD4 T cells (Nakaya et al., 2014).”
• The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight (2019, background): “Additionally, DNA methylation analysis revealed epigenetic discordance (indicated by JSD peaks) for TW in the promoters of NOTCH3, a wellknown regulator of T cell differentiation (34), and SLC1A5/ASCT2, which promotes T cell activation (35), between preflight (L−162) and inflight samples (FD259 forN”
• The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. (2015, background): “Upon activation, naive T cells shift to- ward a pro-growth metabolic program characterized by increased glucose and amino acid metabolism (Carr et al., 2010; Frauwirth et al., 2002; Nakaya et al., 2014; Sinclair et al., 2013; Wang et al., 2011).”
• Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy. (2020, background): “Additionally, genetic loss of the glutamine transporter protein ASCT2 in T cells resulted in impaired generation and function of Th1 and Th17 cells, whereas Tregs were not altered (Nakaya et al., 2014).”