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

Abstract

CD4pos 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 (Linneg) 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 MPPtype2 cells, was defined by expression of Sca-1 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 Il17e-/- mice. The ability of IL-25 to induce the emergence of an MPPtype2 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.

Immunity to gastrointestinal nematode infections

“…Whereas neurons relay their signals via the neurotransmitter neuromedin U, 23 14,32,33 that strongly synergize and prompt the release of IL-4, IL-5, IL-9, and IL-13 from various sources, notably type 2 innate lymphoid cells (ILC2). [15][16][17]25,[34][35][36][37][38] Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells. [15][16][17]31,[34][35][36][37] As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris, 26 T. spiralis, 39 N. brasiliensis, 25,27,40 and H. polygyrus 28 worms.…”

“…[15][16][17]25,[34][35][36][37][38] Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells. [15][16][17]31,[34][35][36][37] As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris, 26 T. spiralis, 39 N. brasiliensis, 25,27,40 and H. polygyrus 28 worms. Furthermore, exogenous administration of IL-25 fails to restore expulsion in il13 À / À mice, 25,27 whereas the reverse is true, 15,17 illustrating that IL-25 acts upstream of IL-13 rather than directly on expulsion.…”

Group 2 Innate Lymphoid Cells in Health and Disease

“…These studies were the first to uncover a previously unrecognized population of ILC2s that promotes type 2 cytokine-mediated immunity. Around the same time, an ILC2-like population, named multipotent progenitor type 2 (MPP type2 ) cells, was also identified and shown to promote type 2 cytokine-mediated immunity to helminth infection (Saenz et al 2010). Subsequently, MPP type2 cells have been distinguished from ILC2s by their preferential responsiveness to IL-25 rather than IL-33, their progenitor-like phenotype, and their ability to differentiate into multiple granulocyte populations .…”

Systemically dispersed innate IL-13–expressing cells in type 2 immunity

“…Conversely, deficiency in IL-25 leads to diminished IL-4, IL-5, and IL-13 production and variable delays in worm clearance in different helminth models (12, 13). Similarly, mice unable to respond to IL-33 because of deficiency in the T1-ST2 subunit of the IL-33 receptor display diminished Th2-associated cytokines and decreased granuloma formation after injection of Schistosoma mansoni eggs (14).Some of the original descriptions of these cytokines as well as more recent reports have noted the capacity of exogenous IL-25, IL-33, or helminth infection to induce the proliferation of a novel non-T/non-B cell population (6,9,12,(15)(16)(17). Although the surface phenotype of these cells has not been firmly established, there seems to be a consensus that these cells are negative for standard lineage markers and have a size and morphology that suggests a lymphoid origin.…”