IL-25 elicits a multi-potent progenitor cell population that promotes Th2 cytokine responses

CD4(pos) T helper (Th) 2 cells secrete interleukin (IL)-4, IL-5 and IL-13 and are required for immunity to gastrointestinal helminth infections1. However, Th2 cells also promote chronic inflammation associated with asthma and allergic disorders2. The non-hematopoietic cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 (IL-17E) have been implicated in inducing Th2 cell-dependent inflammation at mucosal sites3-6, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL-25, a member of the IL-17 cytokine family, promotes the accumulation of a lineage negative (Lin(neg)) multi-potent progenitor (MPP) cell population in the gut-associated lymphoid tissue (GALT) that promotes Th2 cytokine responses. The IL-25-elicited cell population, termed MPP(type2) cells, was defined by expression of Sca-1 and intermediate expression of c-kit (c-kit(int)) and exhibited multi-potent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPP(type2) cells were competent antigen presenting cells and adoptive transfer of MPP(type2) cells could promote Th2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il17e(-/-) mice. The ability of IL-25 to induce the emergence of an MPP(type2) cell population identifies a link between the IL-17 cytokine family and extramedullary hematopoiesis and suggests a previously unrecognized innate immune pathway that promotes Th2 cytokine responses at mucosal sites.