PDF(Pubmed)
Abstract：
Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.
摘要：
2型先天淋巴细胞（ILC2）在肺中引发早期过敏性炎症，但促进2型炎症随后消退和防止ILC2激活延长的因素尚不完全清楚.在这里，我们表明SLAM家族受体（SFR）在此过程中起着至关重要的作用。我们证明了木瓜蛋白酶诱导的小鼠2型免疫过程中ILC2s上几种SFR的动态表达。SFR缺乏加剧ILC2驱动的肺嗜酸性粒细胞浸润，并导致仅在纵隔淋巴结（MLN）中通过ILC2s产生的IL-13显着增加，导致树突状细胞（DC）和TH2细胞数量增加。在MLN中，我们观察到ILC2s和旁观者T细胞之间更频繁的相互作用，T细胞表达的SFR（尤其是SLAMF3和SLAMF5）作为自身配体，抑制ILC2s产生IL-13。机械上,SFRs在ILC2s和T细胞之间的界面上的同型参与主要由SHIP-1介导的抑制性信号传导。这阻止了NF-κB的激活，由IL-7和IL-33驱动，ILC2介导的2型免疫的两个主要驱动因素。因此，我们的研究表明，ILC2-DC-TH2调节轴可能促进肺部2型免疫反应的消退，并强调SLAMF3/SLAMF5是改善2型免疫的潜在治疗靶标。
