Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation.
Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation.
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DOI：
10.1016/j.immuni.2015.05.019
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发表时间：
2015-07-21
期刊：
影响因子：
32.4
通讯作者：
Locksley RM
中科院分区：
文献类型：
--
作者：
Molofsky AB;Van Gool F;Liang HE;Van Dyken SJ;Nussbaum JC;Lee J;Bluestone JA;Locksley RM
第二组固有淋巴样细胞(ILC2)和调节性T细胞(Treg)是由蠕虫感染系统诱导的，但也维持脂肪组织的代谢动态平衡，并在损伤过程中促进组织修复。在这里，我们显示白介素33(IL-33)介导ILC2和Treg细胞在静息脂肪组织中的激活，但也在蠕虫感染或IL-2治疗后激活。出乎意料的是，ILC2内源性IL-33的激活是Treg细胞在体内积累所必需的，并且独立于ILC2 2型细胞因子，但部分依赖于通过ICOSL-ICOS的直接共刺激相互作用。干扰素-γ抑制IL-33在感染组织和脂肪组织中对ILC2的激活和Treg细胞的积聚，这种抑制作用随着年龄和高脂饮食诱导的肥胖而增加。IL-33和ILC2是促进组织和代谢动态平衡的2型免疫反应的中枢介质，而干扰素-γ抑制这一途径，可能促进炎症反应并转移保护宿主所需的代谢资源。IL-33激活和干扰素-γ抑制ILC2引导Treg细胞和2型免疫反应。在静止的脂肪组织中，有蠕虫的活跃损伤或干扰部位，或在IL-2治疗期间，IL-33直接促进ILC2和Treg细胞的聚集和功能。IL-33的ILC2内源性激活是Treg细胞积累所必需的，并部分通过ICOSL/ICOS相互作用发生。ILC2和Treg细胞共同维持嗜酸性粒细胞和激活的巨噬细胞，促进组织修复和动态平衡。在与细菌和病毒感染、肥胖或衰老相关的炎症期间，干扰素-γ抑制ILC2的激活和增殖，限制IL-33介导的ILC2和Treg细胞反应，同时促进Th1免疫反应。
Group 2 innate lymphoid cells (ILC2) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show interleukin-33 (IL-33) mediates activation of ILC2 and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo, and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2 are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host. IL-33 activates and IFN-γ represses ILC2 to direct Treg cell and type 2 immune responses. In resting adipose tissue, sites with active damage or perturbation by helminths, or during IL-2 therapy, IL-33 directly promotes the accumulation and function of ILC2 and Treg cells. ILC2-intrinsic activation by IL-33 is required for Treg cell accumulation, and occurs in part via ICOSL/ICOS interactions. Together, ILC2 and Treg cells maintain eosinophils and alternatively activated macrophages that promote tissue repair and homeostasis. During inflammation associated with bacterial and viral infections, obesity, or aging, IFN-γ represses ILC2 activation and proliferation and limits IL-33-mediated ILC2 and Treg cell responses while promoting a Th1 immune response.