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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.
Highlights
Natural killer (NK) cells are innate lymphoid cells (ILCs) that contribute to immunity through direct lysis of tumor or virus infected cells and though the secretion of immune-regulatory cytokines
When bone marrow-derived dendritic cells (BMDCs) were infected with Listeria monocytogenes (Lm) or stimulated with a recombinant protein corresponding to the “L1S” region of the Lm p60 virulence protein they induced IL-10 production from the purified NK cells (Figure 1A)
Since IL-15C is not known to signal directly through IL-10R, these findings suggest that feedback through NK cell IL-10R promotes both cell expansion and STAT3-dependent IL-10 secretion in mice responding to IL-15C
Summary
Natural killer (NK) cells are innate lymphoid cells (ILCs) that contribute to immunity through direct lysis of tumor or virus infected cells and though the secretion of immune-regulatory cytokines. In a number of animal infection models, NK cell secretion of IFNγ peaks within the first day of infection and promotes inflammatory responses that can contribute to pathogen clearance [1,2,3,4,5,6,7]. IL-10 is produced by both human and mouse NK cells in response to diverse microbial stimuli [8,9,10,11,12,13]. IL-10 secretion potently limits host protection during Lm, Leishmania, and Toxoplasma infections [14,15,16], presumably through inhibitory effects on recruitment or activation of inflammatory myeloid cells [14]. The immune-dampening effects of NK cell IL-10 production are protective in the context of experimental cerebral malaria (ECM) [8]. Strategies to manipulate NK cell IL-10 production could prove useful in treatment of diverse infectious diseases
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