IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

Type-2 immunity, the ancient defence mechanism that provides protection against gastrointestinal helminth infections, involves the recruitment of T helper (TH) cells that produce immune mediators or cytokines to coordinate an immune response involving IgE antibody production, the recruitment of eosinophils and goblet cell hyperplasia. Two groups reporting in this issue have characterized innate type 2 effector leukocyte populations that promote TH2 cytokine responses. Saenz et al. describe multipotent progenitor type-2 (MPPtype2) cells that accumulate in response to the cytokine IL-25 (interleukin-25) and give rise to macrophage or granulocyte lineages promoting TH2 differentiation. Neill et al. describe 'nuocytes', induced by IL25 and IL33, which are the predominant early source of IL13 during a helminth infection. In News & Views, Gérard Eberl discusses how these two papers — and a third in Nature Reviews Immunology ( http://go.nature.com/sJ9D77 ) — influence current thinking on the role of innate immunity. Several non-haematopoietic-cell-derived cytokines, including interleukin (IL)25, have been implicated in inducing T helper 2 (TH2) cell-dependent inflammation, but their precise role has been unclear. Here, IL25 is shown to promote the accumulation of multipotent progenitor cells in gut-associated lymphoid tissue. These cells can give rise to macrophage or granulocyte lineages that promote the differentiation of TH2 cells and contribute to protective immunity against helminth infections. CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections1. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders2. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing TH2 cell-dependent inflammation at mucosal sites3,4,5,6, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin-) multipotent progenitor (MPP) cell population in the gut-associated lymphoid tissue that promotes TH2 cytokine responses. The IL25-elicited cell population, termed MPPtype2 cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kitint), and exhibited multipotent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPPtype2 cells were competent antigen presenting cells, and adoptive transfer of MPPtype2 cells could promote TH2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25-/- mice. The ability of IL25 to induce the emergence of an MPPtype2 cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes TH2 cytokine responses at mucosal sites.