265 : Cooperative activation of innate lymphoid type 2 cells (ILC2) by epithelial cytokines in response to chitin

Chitin, a polysaccharide component of several allergenic and parasitic organisms, initiates type 2 lung inflammation characterized by eosinophils and alternatively activated macrophages (AAMs) but the contribution of signals generated at epithelial barriers is unclear. Using genetic approaches for in vivo tracking and deletion, we show that chitin induces interleukin (IL)-5 and IL-13 secretion from innate lymphoid type 2 cells (ILC2) in a manner dependent on combined expression of a trio of epithelial cytokines, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). These epithelial cytokines are all required for optimal ILC2-derived cytokine expression, which differentially mediate downstream cell accumulation, as both IL-5 and IL-13 contribute to eosinophilia, while IL-13 alone controls AAM induction. Specific cytokine-mediated deletion of ILC2 by either IL-5 or IL-13 expression ablates the chitin-induced lung accumulation of both eosinophils and AAM, and intact chitin is required for ILC2 function as cytokine expression is abrogated by transgenic overexpression of acidic mammalian chitinase. Further, in the combined genetic absence of IL-25, TSLP-R, and the IL-33 receptor subunit T1/ST2, we find that ILC2 develop and populate the lung normally; however, upon innate stimulation with chitin these cells fail to produce critical levels of IL-5 and IL-13 necessary to sustain both eosinophils and AAMs, even while induction of other inflammatory cytokines and cell types are unaffected. Thus, lung ILC2 comprise a cellular conduit that integrates multiple epithelial inputs required for the recruitment and maintenance of specific innate myeloid effector cells upon sensing a widespread environmental polysaccharide.