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.
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We thank members of the Artis laboratory for constructive discussions, M. Abt, D. Hill, G. Sonnenberg, P. Giacomin, M. Nair and K. Walsh for critical reading of the manuscript, and T. Chi and J. J. Bell for invaluable assistance with reagents and experimental design. Work in the Artis laboratory is supported by the National Institutes of Health (AI61570, AI074878 and AI083480 to D.A., F31 training grant GM082187 to S.A.S., and T32 training grant AI007532-08 to J.G.P.), the Burroughs Wellcome Fund (to D.A.), a National Institute of Diabetes and Digestive Kidney Disease Center Grant (P30 DK50306) and pilot grants from the University of Pennsylvania (URF, VCID and PGI) (to D.A.).
J.E.T. and A.L.B. are stockholding employees of Amgen. M.A.K. and R.A.K. are employees of SPB, a subsidiary of Merck&Co.
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Saenz, S., Siracusa, M., Perrigoue, J. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010). https://doi.org/10.1038/nature08901
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