Dendritic cells can prime naïve CD4+ T cells, however we demonstrate that DC-mediated priming is insufficient for the development of TH2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed MHC class II and Il4 message following helminth infection. Basophilia was promoted by thymic stromal lymphopoietin (TSLP) and depletion of basophils impaired immunity to helminth infection. In vitro, basophils promoted antigen-specific CD4+ T cell proliferation and IL-4 production and transfer of basophils augmented the expansion of helminth-responsive CD4+ T cells in vivo. Collectively, these studies suggest that MHC class II-dependent interactions between basophils and CD4+ T cells promote TH2 cytokine responses and immunity against helminth infection.

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.

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.

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A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD.