The lower incidence of allergy and autoimmune diseases in developing countries has been associated with a high prevalence of parasitic infections. Here we provide direct experimental evidence that parasites can exert bystander immunosuppression of pathogenic T cells that mediate autoimmune diseases. Infection of mice with Fasciola hepatica resulted in recruitment of dendritic cells, macrophages, eosinophils, neutrophils, and CD4+ T cells into the peritoneal cavity. The dendritic cells and macrophages in infected mice expressed IL-10 and latency-associated peptide, and they had low surface expression of costimulatory molecules and/or MHC class II. Furthermore, most CD4+ T cells in the peritoneal cavity of infected mice secreted IL-10, but not IFN-γ or IL-4. There was a less significant expansion of CD4+Foxp3+ T cells. F. hepatica-specific Tr1-type clones generated from infected mice suppressed proliferation and IFN-γ production by Th1 cells. Infection was associated with suppression of parasite-specific Th1 and Th2 responses, which was reversed in IL-10-defective mice. Infection with F. hepatica also exerted bystander suppression of immune responses to autoantigens and attenuated the clinical signs of experimental autoimmune encephalomyelitis. Protection was associated with suppression of autoantigen-specific IFN-γ and IL-17 production. The suppression of Th1 and Th17 responses and attenuation of experimental autoimmune encephalomyelitis by F. hepatica was maintained in IL-10−/− mice but was reversed by neutralization of TGF-β in vivo. Our study provides evidence that F. hepatica-induced IL-10 subverts parasite-specific Th1 and Th2 responses, but that F. hepatica-induced TGF-β plays a critical role in bystander suppression of autoantigen-specific Th1 and Th17 responses that mediate autoimmune diseases.

Helminth parasites are highly successful pathogens, chronically infecting a quarter of the world's population, causing significant morbidity but rarely causing death. Protective immunity and expulsion of helminths is mediated by T-helper 2 (Th2) cells, type 2 (M2) macrophages, type 2 innate lymphoid cells, and eosinophils. Failure to mount these type 2 immune responses can result in immunopathology mediated by Th1 or Th17 cells. Helminths have evolved a wide variety of approaches for immune suppression, especially the generation of regulatory T cells and anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. This is a very effective strategy for subverting protective immune responses to prolong their survival in the host but has the bystander effect of modulating immune responses to unrelated antigens. Epidemiological studies in humans have shown that infection with helminth parasites is associated with a low incidence of allergy/asthma and autoimmunity in developing countries. Experimental studies in mice have demonstrated that regulatory immune responses induced by helminth can suppress Th2 and Th1/Th17 responses that mediate allergy and autoimmunity, respectively. This has provided a rational explanation of the 'hygiene hypothesis' and has also led to the exploitation of helminths or their immunomodulatory products in the development of new immunosuppressive therapies for inflammatory diseases in humans.

Innate Lymphoid Cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We employed inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions, however RORα was sufficient to support robust IL-22 production among the LTi-like ILC3 subset, but not NCR + ILC3s. LTi-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR + ILC3s, which co-express T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs post-development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

Epidemiologic studies in humans have demonstrated that infection with helminth parasites is associated with a reduced risk of developing autoimmune diseases. Mechanistic studies in mice have linked the protective effect of helminths on autoimmunity to the suppressive activity of helminth-induced regulatory T cells (Tregs) or Th2 cells. In this study, we demonstrate that treatment of mice with Fasciola hepatica excretory-secretory products (FHES) attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Protection was associated with a significant reduction in the infiltration of pathogenic Th1 and Th17 cells into the brain. Although FHES enhanced anti-inflammatory cytokine and Th2 responses, protection against EAE was independent of IL-4, IL-10, and Tregs. However, administration of FHES induced production of the type 2 cytokines IL-33 and IL-5, which promoted accumulation of eosinophils. FHES-induced expansion of eosinophils and protection against EAE was lost in IL-33−/− mice and upon neutralization of IL-5. Furthermore, transfer of FHES-induced or IL-33–induced eosinophils conferred protection against EAE. In addition, treatment of mice with recombinant IL-33 attenuated autoimmunity, and this was dependent on IL-5. To our knowledge, this study is the first to report a role for helminth-induced IL-5 and IL-33 in protection against autoimmunity.