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

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02087

DOI=10.3389/fimmu.2019.02087

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Listeria monocytogenes</italic> (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional <italic>Stat3</italic> 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 <italic>Stat3</italic> while NK cell-intrinsic deficiency for <italic>Stat3, Il15ra</italic>, or <italic>Il10ra</italic> abrogated NK cell IL-10 production and increased resistance against Lm. NK cell <italic>Stat3</italic> 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.</p>