Epithelial Cell-Specific Act1 Adaptor Mediates Interleukin-25-Dependent Helminth Expulsion through Expansion of Lin−c-Kit+ Innate Cell Population

SummaryInterleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell type-specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin−c-Kit+ innate cell population in the mesenteric lymph node, lung, and liver. Th2 cell-inducing cytokine (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin−c-Kit+ cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin−c-Kit+ innate cell population through the positive-feedback loop of IL-25, initiating the type 2 immunity against helminth infection.

► Epithelial cell-specific Act1 is critical for IL-25-dependent helminth expulsion ► Act1 in epithelium is required for IL-25-induced expansion of Lin−c-Kit+ cells ► Epithelial cells produce IL-25, etc., to induce the expansion of the Lin−c-Kit+ cells ► Lin−c-Kit+ cells rescued type 2 immunity in epithelial-specific Act1-deficient mice