Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Suita, Japan.
Life Sci Alliance. 2022 Aug 29;5(11). doi: 10.26508/lsa.202201486. Print 2022 Nov.
Group 2 innate lymphoid cells (ILC2s) have been implicated in both physiologic tissue remodeling and allergic pathology, yet the niche signaling required for ILC2 properties is poorly understood. Here, we show that an axonal guidance cue semaphorin 6D (Sema6D) plays critical roles in the maintenance of IL-10-producing ILC2s. mice exhibit a severe steady-state reduction in ILC2s in peripheral sites such as the lung, visceral adipose tissue, and mesentery. Interestingly, loss of Sema6D results in suppressed alarmin-driven type 2 cytokine production but increased IL-10 production by lung ILC2s both in vitro and in vivo. Consequently, mice are resistant to the development of allergic lung inflammation. We further found that lung mesenchymal cells highly express Sema6D, and that niche-derived Sema6D is responsible for these phenotypes through plexin A1. Collectively, these findings suggest that niche-derived Sema6D is implicated in physiological and pathological characteristics of ILC2s.
2 型固有淋巴细胞 (ILC2) 被认为与生理组织重塑和过敏病理有关，但对于 ILC2 特性所需的生态位信号知之甚少。在这里，我们表明轴突导向信号分子 semaphorin 6D (Sema6D) 在维持产生 IL-10 的 ILC2 中发挥关键作用。Sema6D 缺陷小鼠在肺、内脏脂肪组织和肠系膜等外周部位表现出 ILC2 的严重稳态减少。有趣的是，Sema6D 的缺失导致警报素驱动的 2 型细胞因子产生受到抑制，但肺 ILC2 的 IL-10 产生增加，无论是在体外还是体内。因此，Sema6D 缺陷小鼠对过敏性肺炎症的发展具有抗性。我们进一步发现，肺间充质细胞高度表达 Sema6D，而龛位衍生的 Sema6D 通过 plexin A1 负责这些表型。总之，这些发现表明，龛位衍生的 Sema6D 与 ILC2 的生理和病理特征有关。
