Neonatal helminth infection and chronic type 2 inflammation promotes immune suppression through FcγRIIb

Allergic diseases are rising in industrialized countries. This contrasts with rural communities where decreased allergic incidence correlates with increased prevalence of intestinal helminth infections. While helminths and their byproducts can ameliorate allergic inflammation in adult mice with established disease, it remains unknown if early-life exposure can prevent or delay allergic disease onset. We utilized a neonatal infection model with the gastrointestinal helminth Heligmosomoides polygyrusand found that neonatal H. polygyruscolonization results in chronic infection and type 2 inflammation. This study investigates how chronic and systemic type 2 hallmarks IL-4 and IgG1 may be involved in the long-term suppressive mechanisms induced by neonatal helminth colonization. We hypothesize that IL-4-induced upregulation of the sole inhibitory Fc receptor, FcγRIIb, allows for sustained suppression of T cell mediated inflammation by increasing the activation threshold of antigen presenting cells. Increasing this threshold prevents allergen-specific T cells from becoming optimally activated and instead promotes T cell tolerance. In addition to IL-4 increasing expression of FcγRIIb on macrophages, it promotes the production of its ligand IgG1, completing the suppressive circuit. This model predicts that elimination of FcγRIIb and/or IL-4 will result in greater T cell activation and allergic inflammation. Our in vivoand in vitrodata show that FcγRIIb is necessary for reducing allergic airway inflammation and T cell activation after allergen challenge. Taken together, these data support a model in which chronic helminth infection naturally mimics the suppressive effects of intravenous immunoglobulin therapy. Supported by the National Institutes of Health NIAID training grant (Training Program in Immunology; T32-AI07405)