期刊
IMMUNITY
卷 54, 期 11, 页码 2514-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2021.10.009
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资金
- NIH [AI 110481]
- German Research Foundation (DFG) [SFB1160]
- DFG under Germany's Excellence Strategy (CIBSS EXC-2189) [390939984]
- Alexander von Humboldt Fellowship Foundation
- Swiss National Science Foundation
- Japan Society for the Promotion of Science
- DK Cell Communication in Health and Disease [W 1205-B09]
- DFG [TRR130, 12]
- Max Planck Society
IL-3-induced expression of amino acid transporters in pDCs activates mTORC1 nutrient sensor, leading to cytokine production. Inhibition of amino acid transporters and ENPP2 can block cytokine production, providing additional therapeutic targets for autoimmune diseases involving pDCs.
Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2 dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated.
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