Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 11; pp. 2514 - 2530.e7
• Main Authors: Grzes, Katarzyna M., Sanin, David E., Kabat, Agnieszka M., Stanczak, Michal A., Edwards-Hicks, Joy, Matsushita, Mai, Hackl, Alexandra, Hässler, Fabian, Knoke, Kristin, Zahalka, Sophie, Villa, Matteo, Kofler, David M., Voll, Reinhard E., Zigrino, Paola, Fabri, Mario, Pearce, Erika L., Pearce, Edward J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-11-2021
• Subjects: Amino Acid Transport Systems - genetics; Amino Acid Transport Systems - metabolism; amino acid transporters; Autoimmunity; Biomarkers; cytokines; Cytokines - genetics; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Susceptibility; Energy Metabolism; Gene Expression Regulation; GM-CSF; Humans; IL-3; Immunity; JAK-STAT signaling; metabolism; mTORC1; plasmacytoid dendritic cells; Signal Transduction; plasmacytoid dendritic cells; autoimmunity; GM-CSF; JAK-STAT signaling; metabolism; cytokines; IL-3; mTORC1; amino acid transporters
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.10.009

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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•IL-3 induces JAK2-STAT5-dependent expression of SLC7A5 and SLC3A2 in pDCs•Leucine uptake via SLC7A5 and SLC3A2 primes mTORC1 for activation by TLR agonists•pDCs activated by TLR agonists express SLC7A11 and ENPP2•Inhibitors of JAK2, SLC7A5, SLC7A11, and ENPP2 prevent cytokine production by pDCs
The mechanism by which IL-3 supports human pDC biology is unclear. Grzes et al. show that IL-3 induces system L amino acid transporter expression, thereby priming mTORC1 to allow metabolic upregulation and cytokine production in response to TLR agonists.