|SAENZ, STEVEN - University Of Pennsylvania|
|SIRACUSA, MARK - University Of Pennsylvania|
|PERRIGOUE, JACQUELINE - University Of Pennsylvania|
|SPENCER, SEAN - University Of Pennsylvania|
|TOCKER, JOEL - University Of Pennsylvania|
|BUDELSKY, ALISON - University Of Pennsylvania|
|KLEINSCHEK, MELANIE - Schering-Plough Research|
|KAMBAYASHI, TAKU - University Of Pennsylvania|
|ARTIS, DAVID - University Of Pennsylvania|
Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2010
Publication Date: 4/29/2010
Citation: Saenz, S.A., Siracusa, M.C., Perrigoue, J.G., Spencer, S.P., Urban Jr, J.F., Tocker, J.E., Budelsky, A.L., Kleinschek, M.A., Kambayashi, T., Artis, D. 2010. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature. 464(7923):1362-1366.
Interpretive Summary: More than one third of the world’s population is infected with gastrointestinal roundworms (worms). In general, most enteric nematodes induce an elevation of Th2 cytokines linked to protective immunity against worm infection. This response is also linked to allergic disease seen in Westernized societies. The rising prevalence of autoimmune diseases including diabetes, inflammatory bowel disease, and celiac disease, is mirrored by the decreasing incidence of worm infection in Westernized societies and this has been attributed, in part, to the polarity of Th cell responses. This relationship between the epidemiology of these diseases forms the basis for the ‘‘hygiene hypothesis’’ that links improvements in hygienic measures to an increase in autoimmune and allergic diseases. Although this concept does not address the influence of other factors such as environmental pollutants or changes in diet, it does support the importance of polarized Th cell cytokine profiles in intestinal health. The protective effects of worm infection were attributed to the well-documented ability of Th2 cytokines to down-regulate pro-inflammatory Th1 cytokine production or to promote the development of T regulatory cells. These features are studied to show the source of cells producing these molecules in the intestine. It also describes the major regulatory mechanisms in the immune system that control the balance of cytokines that affect autoimmune pathologies and the normal immune balance and nutrient absorption that are characteristic of good intestinal function.
Technical Abstract: CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. 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 sites, 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 (Lin2) multi-potent 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 multi-potent 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 extra-medullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes TH2 cytokine responses at mucosal sites.