Synergy between Common γ Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation

Abstract

Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose–response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen–antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.

TnI and IL-18 levels are associated with prognosis of sepsis

“…IL-18, a preinflammatory mediator discovered in recent years, can regulate proinflammatory cytokine release and intercellular adhesive molecule expression 23. Evidence shows that IL-18 can promote the generation of interferon-γ by inducing the Th1 cells to enhance T cell activity and increase the toxic effect of cells 24. For patients with sepsis, IL-18 may be correlated with the general infectious responses, but no evidence clarifies the correlation.…”

Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

“…Indeed, IL-18+IL-12 synergistically induced high levels of IL- We report that IL-15 and IL-2 additionally enhance IL-8 production by stimulated NK cells, which suggests that the IL-8 response may be enhanced in an in vivo context in which these cytokines are present , and in immunotherapies in which NK cells are preactivated with IL-18/IL-15/IL-12. The enhancement of IL-8 production by these common γ-chain cytokines is likely attributable to the previous finding that common γ-chain cytokines are capable of synergizing with IL-18 to activate NK cells [27] . Our findings indicate a potential role for the K562-mb-IL-21 cells in culture to prime expanded NK cells for IL-8 production since they express membrane-bound IL-21, another common γ-chain cytokine.…”

“…IL-15 and IL-2 are known NK cell activators and survival factors and they have been shown to synergize with IL-18 and IL-12 [27] . Furthermore, IL-18+IL-12 stimulation has been shown to upregulate the expression of a highaffinity IL-2 receptor on NK cells, enhancing the sensitivity of NK cells to IL-2 [28] .…”

The evolution of the molecular response to stress and its relevance to trauma and stressor-related disorders

“…More specifically, combat-exposed men with PTSD exhibit an aberrant profile of NK cells, a key component of the innate immune system (Bersani et al, 2016). Moreover, Nielsen et al (2016) describe the involvement of cytokines in the function of NK cells and these two studies, as well as the extensive involvement of cytokines in the immune system provide evidence of a clear association of PTSD and the immune system. prospectively associated with PTSD symptom emergence, and that individuals with lesser inflammatory activity may be relatively resilient while those with greater inflammatory activity may be more vulnerable to developing PTSD symptoms.…”