Th17-Treg Antagonism: Impact on Disease Outcome in Helminth Infections

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This project will investigate the molecular mechanisms involved in the induction of IgG4 subclass of immunoglobins by regulatory T-cells (Treg). Treg are important mediators of the well-known phenomena of immune suppression. There are distinct subgroups of antigenspecific and naturally occurring Treg that are induced in allergy during hypo-sensibilisation, in chronic infection like hepatitis C, or parasite infections. Our group described the occurrence at high frequency of antigen-specific Treg in human onchocerciasis, which was the first description of Treg in human infections at all. Subsequently, we have found that Treg clones selectively induce the synthesis of IgG4 when co-cultured with purified B cells. IgG4 are antiinflammatory and are up-regulated in allergy and chronic diseases, e.g. worm diseases. Based on our earlier results, the present project aims to find the molecular mechanisms of Treg-B cell interactions, and to determine which molecules (GITR, CTLA-4, ICOS, TLR etc., see Objectives) induce or inhibit these interactions. This work will be performed using cells from healthy donors stimulated with tetanus toxoid as antigen-model, and cells generated from onchocerciasis patients to extend the findings to a chronic helminth infection. These samples are available from earlier studies. The results from the project should have important implications for infectious diseases but also for allergy and auto-immune disorders.