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

Abstract

Natural killer (NK) cells can produce IFNg 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. 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-15Ra. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Ra. Survival-promoting effects of IL-15C treatment in experimental cerebral malaria dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increases resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNg, 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.