Mast cell-driven clearance in N. brasiliensis is masked by IL-25-dependent B1 cell IgE.

Abstract

Abstract A large amount of poly-specific IgE is generated during helminth infection. We have previously shown that innate-like B1 cells are responsible for this IgE production during infection with the nematode parasite Nippostrongylus brasiliensis. In vitro analysis demonstrated a novel role for IL-25-enhancement of IgE in B1 cells from helminth infected mice. In T cell-reconstituted RAG1−/− mice, N. brasiliensis clearance was enhanced with the addition of B2 cells in an IgE-dependent manner. This enhanced clearance was impeded by reconstitution with IgE sufficient B1 cells. IL-25 receptor-deficient B1 cells did not impede this clearance. Mucosal mast cells mediated the B2 cell-enhancement of clearance only in the absence of B1 cells. This was shown using mast cell depletion with anti-ckit (ACK.2) in a helminth-infected RAG1−/− reconstitution model. Additionally, gene expression analysis of the jejunum on day 7 post-inoculation found increased mast cell protease genes and mucus related genes in RAG1−/− mice reconstituted with B2 cells over T cells alone. This revealed a potential mechanism for B2 cell-enhanced clearance. Finally, R1E4, an antibody that prevents IgE from binding to FcɛRI, was administered in a model of RAG1−/− reconstitution infected with helminth and results confirmed that the B2 cell IgE/mast cell clearance enhancement was mediated through FcɛRI. Overall, these data shine new light on B2 cell derived IgE and mast cells and their role in helminth clearance that is impeded by IL-25-driven B1 cell IgE.