IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.

IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.

Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the anti-microbial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process. We identified IL-18 as a cytokine that cooperates with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, as well as induce and maintain IL-22 production. To determine a mechanism of action, we examined the NF-κB pathway, which is activated by IL-18 signaling. We found that the NF-κB complex signaling component, p65, binds to the proximal region of the IL22 promoter and promotes transcriptional activity. Finally, we observed that CD11c+ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils in situ. Therefore, we identify a new mechanism by which human ILC3s proliferate and produce IL-22, and identify NF-κB as a potential therapeutic target to be considered in pathologic states characterized by overproduction of IL-18 and/or IL-22.

第3组先天性淋巴细胞（ILC3s）是免疫系统的重要调节因子，在共生菌存在的情况下维持内稳态，但在应对微生物病原体时激活免疫防御。ILC3s是白细胞介素 - 22（IL - 22）的一个强大来源，IL - 22是一种对刺激抗菌反应至关重要的细胞因子。我们试图确定能够促进ILC3s增殖并诱导或维持其产生IL - 22的细胞因子，并确定这一过程的分子机制。我们发现白细胞介素 - 18（IL - 18）是一种与ILC3存活因子白细胞介素 - 15（IL - 15）协同作用的细胞因子，可诱导人ILC3s增殖以及诱导和维持IL - 22的产生。为了确定作用机制，我们研究了由IL - 18信号激活的核因子 - κB（NF - κB）通路。我们发现NF - κB复合物信号成分p65与IL22启动子的近端区域结合并促进转录活性。最后，我们观察到在人扁桃体原位中，表达IL - 18的CD11c⁺树突状细胞与ILC3s紧密相邻。因此，我们确定了人ILC3s增殖和产生IL - 22的一种新机制，并确定NF - κB是在以IL - 18和/或IL - 22过度产生为特征的病理状态中可考虑的潜在治疗靶点。