ABSTRACT
ADAM17 is known to contribute to the immune system through its shedding of tumor necrosis factor alpha (TNFα). However, the role of ADAM17 in B cell biology is not well characterized. To determine whether B cell ADAM17 contributes to T cell-independent humoral immune responses, we crossed CD19 Cre transgenic mice with mice bearing a floxed allele of ADAM17 (ADAM17CD19). In this study, we show a B cell intrinsic role for ADAM17 in regulating marginal zone B cell (MZB) numbers in mice. Interestingly, we demonstrate that the loss of B cell ADAM17 results in reduced MZB numbers in the naïve state and after immunization with T-independent antigen, yet enhanced humoral immunity to T cell independent antigens. We additionally find elevated TACI and CD138 levels on plasma cells following immunization in ADAM17CD19 mice. Overall, these findings suggest that B cell ADAM17 may orchestrate T independent immune responses through both MZB numbers and plasma cell antibody production.
Subject(s)
ADAM17 Protein/metabolism , B-Lymphocytes/immunology , Immunity, Humoral , Syndecan-1/metabolism , T-Lymphocytes/immunology , Transmembrane Activator and CAML Interactor Protein/metabolism , Animals , Biomarkers/metabolism , Cell Survival , Immunization , Mice, Transgenic , Plasma Cells/metabolismABSTRACT
The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using B6mir146a-/- mice and a model of lymphoproliferative disease using the well-characterized lpr model. B6lpr mice lacking ADAM10 on B cells (A10Blpr) have decreased nodal proliferation and T cell accumulation compared with control B6lpr mice. Additionally, A10Blpr mice have a drastic reduction in autoimmune anti-dsDNA Ab production. In line with this, we found a significant reduction in follicular helper T cells and germinal center B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only show a role of B cell ADAM10 in control autoimmunity but also increase our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity.
