Immunity | ASCT2介导的谷氨酸摄取影响T细胞的功能
Inflammatory T Cell Responses Rely on Amino Acid Transporter ASCT2 Facilitation of Glutamine Uptake and mTORC1 Kinase Activation
Mako Nakaya,1 Yichuan Xiao,1 Xiaofei Zhou,1 Jae-Hoon Chang,1,4Mikyoung Chang,1 Xuhong Cheng,1 Marzenna Blonska,2 Xin Lin,2,3and Shao-Cong Sun1,3,*
Previous paper published <Nature Immunol.2013 May;14(5):500-508> have showed that glutamine was quickly uptaked during T cell activation. However, how this process id mediated is pooly understood. This paper demonstrated that glutamine is vital for Th1 and Th17 responses by deletion the gene ASCT2, which is responsible for glutamine transport. Firstly, they found that upon TCR and CD28 stimulation, Th1 and Th17 differentiation were significantly affected, but not Th2 and Foxp3+ Treg differentiation in vitro. Then they also confirmed the result that ASCT2 deficiency would decrease IFNr and IL17 production through L.monocytogensinfection in vivo. And thus ASCT2 KO mice showed milder EAE phenotype compared to WT mice. Moreover,they identified that ASCT2 could mediate TCR-Stimulated mTORC1 Activation in Naive T Cells. Mechanistically, they found the link between CBM complex and TCR-mediated mTORC1 activation but independent on the downstream target IKK. In summary, the data provides a direction for exploring the amino acids-mediated T cell metabolism and function and Manipulating the metabolic state of T cells may modulate the balance between effector and suppressor functions, potentially opening new avenues for the development of immunotherapies.
Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation
Dorota Klysz et al
Sci. Signal, 2015
When a na?ve CD4+T cell is activated by antigen, glutamine uptake is important for CD4+ T cell activation. The author found that activation of na?ve CD4+ T cells under conditions of glutamine deprivation resulted in their differentiation into Foxp3+ Tregs which depend on TGFbeta signaling. Inhibition of TGF-β signaling would promote Th1 response.Moerover, the induced Foxp3+ Tregs have high proliferation ability and have enhanced suppressive activity after depletion of glutamine in the culture medium. Hence, Foxp3+ T cells generated under glutamine-deficient conditions could inhibit autoimmune colitis. Together, these data suggest that increasing the αKG concentration could enhance mTORC1 signaling, which would support the differentiation of na?ve cells into Th1 cells. From an evolutionary perspective, it is tempting to speculate that it is in the interest of the organism to evade an energetically costly immune response under conditions of amino acid starvation. And indeed,glutamine abundance is reduced in patients with hepatocellular, colon, and stomach tumors, This finding may explain the data that show that Treg cells preferentially accumulate in and around murine tumors, especially as the tumors progress.
Edited by Biaolong Deng