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The center grouping depicts core shared components of ILC2s in a stromal niche that likely applies to resident Th2s in the adapted state. Tissue function is translated by many cell types into signaling pathways that are integrated and thresholded by resident alarmin signals, transmitted in part by stromal niche fibroblasts to ILC2s, which release type 2 cytokines that feed back on niche stromal cells and regulate myeloid cell activation and recruitment. With sufficient perturbation, ILC2s proliferate, increase cytokine outputs, and migrate from the niche to interact with resident cells and tissues. Outer Barriers (upper left) are externally oriented epidermis in skin and mucosa, where ILC2s can be activated by barrier-specific alarmins, like IL-25 in small intestine or TSLP/IL-18 in skin. Outer Barrier tissues are supported by Outer Borders (lower left) consisting of subepithelial fascial planes that support resident ILC2s that, when activated, can facilitate niche enlargement to house recruited Th2 cells and myeloid cells that increase local collagen deposition and reinforce the physical border internal to the external barrier. Inner Borders (upper right) represent serosal mesothelial linings surrounding internal organs, which also support ILC2/stromal niches and use type 2 cytokines to enlarge the niche and enhance structural support. Internal Boundaries (lower right) depict organization of ILC2s in proximity to vascular and ductal structures that allow monitoring of regional homeostasis in tissues.

Although tissue resident ILC2s (pink) and Th2s (blue) derive from upstream precursors, we figuratively represent their origins from populations designated ILC2s or Th2s for illustrative purposes. Tissue ILC2s are comprised of populations originating from primitive hematopoiesis originating in yolk sac and liver and bone-marrow-definitive HSCs. Additional heterogeneity may reflect derivation of some ILC2s from thymic pre-T cell precursors (dotted red borders). Adaptive Th2s arise from definitive adult bone marrow HSCs after thymic education and export as naive T cell precursors. Neonatal adaptive T cells can also arise from fetal HSCs, comprising a small population of tissue cells with rapid effector function (dotted blue borders). The triangles at the top denote the different layering of peripheral tissues at the time of birth in mouse and human.