2. Academic Validation
  3. Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters

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

  • Immunity. 2021 Nov 9;54(11):2514-2530.e7. doi: 10.1016/j.immuni.2021.10.009.
Katarzyna M Grzes 1,  David E Sanin 1,  Agnieszka M Kabat 2,  Michal A Stanczak 1,  Joy Edwards-Hicks 2,  Mai Matsushita 2,  Alexandra Hackl 2,  Fabian Hässler 2,  Kristin Knoke 3,  Sophie Zahalka 4,  Matteo Villa 2,  David M Kofler 5,  Reinhard E Voll 6,  Paola Zigrino 3,  Mario Fabri 3,  Erika L Pearce 7,  Edward J Pearce 8
Affiliations

Affiliations

  • 1 Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany.
  • 3 Department of Dermatology, University of Cologne, Cologne 50931, Germany.
  • 4 Research Laboratory of Infection Biology, Department of Medicine I, Medical University of Vienna, Vienna 1090, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
  • 5 Department I of Internal Medicine, University of Cologne, Cologne 50931, Germany.
  • 6 Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
  • 7 Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
  • 8 Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Faculty of Biology, University of Freiburg, Freiburg 79104, Germany; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA. Electronic address: epearce7@jhmi.edu.
PMID: 34717796 DOI: 10.1016/j.immuni.2021.10.009
Abstract

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.

Keywords

GM-CSF; IL-3; JAK-STAT signaling; amino acid transporters; autoimmunity; cytokines; mTORC1; metabolism; plasmacytoid dendritic cells.

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