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

Katarzyna M. Grzes, David E. Sanin, Agnieszka M. Kabat, Michal A. Stanczak, Joy Edwards-Hicks, Mai Matsushita, Alexandra Hackl, Fabian Hässler, Kristin Knoke, Sophie Zahalka, Matteo Villa, David M. Kofler, Reinhard E. Voll, Paola Zigrino, Mario Fabri, Erika L. Pearce, Edward J. Pearce

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2514-2530.e7
JournalImmunity
Volume54
Issue number11
DOIs
StatePublished - Nov 9 2021

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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