NK Cell IL-10 Production Requires IL-15 and IL-10 Driven STAT3 Activation

Sarah E. Clark, Kristina S. Burrack, Stephen C. Jameson, Sara E. Hamilton, Laurel L. Lenz

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

Original languageEnglish (US)
Article number2087
JournalFrontiers in immunology
Volume10
DOIs
StatePublished - Sep 4 2019

Bibliographical note

Funding Information:
We thank current and former members of our labs for their critical discussion of these studies. Funding. This work was funded by the National Institute of Allergy and Infectious Diseases grants R01-AI131662 and R01AI06563 (LL), R21-AI100088 (SJ and SH), F32-AI120312 (KB), and R01-AI143828 (SH) and support from the University of Minnesota Foundation (SH).

Publisher Copyright:
© Copyright © 2019 Clark, Burrack, Jameson, Hamilton and Lenz.

Keywords

  • IL-10
  • IL-15
  • IL-15 complex
  • Listeria (L.) monocytogenes
  • NK cell
  • Plasmodium
  • Stat3
  • cerebral malaria

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