A tissue checkpoint regulates type 2 immunity. Mus musculus

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. Overall design: ATAC-seq on ILC2 and Tcells from lymph node and lung tissues in WT and cytokine KO