IL-4 and IL-13 modulate natural killer cell responses under inflammatory conditions

• Published in: The Journal of immunology (1950) Vol. 198; no. 1_Supplement; pp. 194 - 194.11
• Main Authors: Ohayon, David E, Krishnamurthy, Durga, Brusilovsky, Michael, Waggoner, Stephen N
• Format: Journal Article
• Language: English
• Published: 01.05.2017
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.194.11

Abstract Natural killer (NK) cells are critical producers of IFN-g and mediators of cytotoxicity in response to type 1 inflammatory cytokine (e.g. IL-12) rich environments. Conventional thinking therefore holds that type 2 cytokines (e.g. IL-4 and IL-13) that counter production of IL-12 would inhibit NK cell effector functions and thereby limit the antiviral role of NK cells. In contrast, IL-4 unexpectedly synergized with IL-12 to enhance IFN-g production by mouse NK cells. We now extend this observation to human NK cells, where we find that stimulation with either IL-4 or IL-13 resulted in dose-dependent enhancement of IFN-g and TNF-a expression in response to IL-12. Neither IL-4 nor IL-13 stimulated IFN-g release in the absence of IL-12, suggesting that these type 2 cytokines modulate IL-12 signaling or NK cell responsiveness to IL-12. In contrast to the effect of IL-4 on IL-12 responsiveness, IL-4 (but not IL-13) markedly reduced the expression of IFN-g and TNF-a by human NK cells following engagement of the natural cytotoxicity receptor, NKp46. Likewise, IL-4-treated NK cells demonstrated reduced cytotoxicity towards K562 cells. Our results reveal that IL-4 and IL-13 modulate NK cells in a complex manner, enhancing responsiveness to inflammatory cytokines like IL-12 while diminishing activation via natural cytotoxicity receptors. We speculate that this could have important consequences for NK cell lysis of eosinophils, IFN-g-mediated airway hyperresponsiveness, and other features of allergic or asthmatic diseases associated with aberrant type 2 cytokine production.