A tissue checkpoint regulates type 2 immunity

Innate pattern recognition receptors for conserved structural elements play critical roles in immunity against viruses, bacteria and fungi, but analogous pathways linking innate recognition of diverse allergens or helminths with type 2 immunity remain elusive. The discovery of group 2 innate lymphoid cells (ILC2s), which produce similar cytokines as CD4+ T helper 2 (Th2) cells1, has suggested models whereby ILC2s directly or indirectly induce adaptive Th2 cells,2-8 but current understanding of how these cells interact in tissue microenvironments to coordinate allergic immunity is limited. Here, we show that tissue Th2 cells differentiate independently of ILC2s, but that both cell types share overlapping transcriptional and functional programs, which require exposure to the tissue-derived cytokines such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Combined loss of these epithelial cytokines affects neither Th2 cell priming nor T cell-dependent antibody production, but abrogates allergic lung inflammation due to requirements for local tissue signals to promote differentiation of effector function in both ILC2s and Th2 cells. Our findings reveal how diverse perturbations, including proteases, venoms and mechanical irritants, converge on common pathways to activate type 2 immune responses, thus uncovering a shared checkpoint that can be exploited to control both innate and adaptive allergic inflammation. ATAC-seq on ILC2 and Tcells from lymph node and lung tissues in WT and cytokine KO

能够识别保守结构元件的固有模式识别受体（innate pattern recognition receptors）在抗病毒、细菌及真菌的免疫防御中发挥核心作用，但将天然免疫识别多种过敏原或蠕虫（helminths）与2型免疫（type 2 immunity）相连的类似通路仍有待阐明。能够产生与CD4+辅助性T细胞2（CD4+ T helper 2, Th2）相似细胞因子的2型固有淋巴细胞（group 2 innate lymphoid cells, ILC2s）的发现¹，提出了ILC2s可直接或间接诱导适应性Th2细胞的模型2-8，但目前学界对这两类细胞如何在组织微环境中相互作用以协调变应性免疫应答的认知仍较为有限。本研究发现，组织内Th2细胞的分化不依赖于ILC2s，但两类细胞共享高度重叠的转录与功能程序，该程序的激活需要暴露于组织源性细胞因子，如白细胞介素（interleukin, IL）-25、IL-33及胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin, TSLP）。联合缺失这些上皮源性细胞因子，既不会影响Th2细胞的致敏过程，也不会干扰T细胞依赖性抗体生成，但会消除变应性肺部炎症——这是因为两类细胞的效应功能分化均依赖局部组织信号的促进。本研究揭示了包括蛋白酶、毒液及机械刺激物在内的多种外界扰动因素如何通过共同通路激活2型免疫应答，从而发现了一个可用于调控天然与适应性变应性炎症的共享调控检查点。对野生型（wild type, WT）与细胞因子基因敲除（knockout, KO）小鼠的淋巴结及肺组织中的ILC2与T细胞开展转座酶可及性测序分析（Assay for Transposase-Accessible Chromatin using sequencing, ATAC-seq）