Inflammatory T Cell Responses Rely on Amino Acid Transporter ASCT2 Facilitation of Glutamine Uptake and mTORC1 Kinase Activation

Abstract

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.

T cell metabolism drives immunity

“…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). Surprisingly, the loss of ASCT2 did not inhibit proliferation or IL-2 production.…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…With regard to this important issue, some insight can be gained from the knockout mouse studies with selective deletion of these transporters. Mice with the deletion of Slc7a11, Slc1a5, and Slc6a14 are viable and fertile with no obviously noticeable phenotype (46)(47)(48). This suggests that pharmacologic blockade of these three transporters may not have any significant impact on normal cells.…”

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…The high-affinity glutamine transporter Slc1a5 is rapidly elevated at both the mRNA and protein levels following lymphocyte stimulation (Nakaya et al, 2014). We therefore examined whether the let7adf cluster affected glutamine uptake and glutamine consumption by regulating Slc1a5.…”