Interleukin-15 Enables Septic Shock by Maintaining Natural Killer Cell Integrity and Function

Abstract

Interleukin-15 (IL-15) is essential for development, differentiation and function of natural killer (NK) and memory (m) CD8⁺T cells. Our lab previously showed that NK and CD8⁺T cells facilitate systemic inflammation and physiological dysfunction during septic shock. However, factors that regulate NK and CD8⁺T cell function during sepsis are not well characterized. We hypothesize that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8⁺T cell numbers and function. To test our hypothesis, the response of IL-15-deficient (IL-15 KO) mice to sepsis was assessed. IL-15 KO mice showed improved survival, attenuated hypothermia, and less pro-inflammatory cytokine production during septic shock caused by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS). Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8⁺ T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15 neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion and conferred protection if given 4 days prior to septic challenge. IL-15 SA treatment amplified septic shock, which was prevented by NK cell or IFNγ depletion. IL-15 SA treatment also exacerbated septic shock caused by CLP if given after the onset of sepsis. In conclusion, endogenous IL-15 doesn’t directly augment the pathogenesis of sepsis but enables septic shock by maintaining NK cell numbers and function. Exogenous IL-15 SA exacerbates severity of sepsis by activating NK cells and facilitating IFNγ production.