Impaired CD1d downregulation on B cells limits the cGVH response in Mertk-/- mice (44.28)

Abstract

Abstract The splenic marginal zone (MZ) contains specialized macrophages and B cells. Activation and migration of MZB into follicular (FO) regions of the spleen has been proposed as one of the mechanisms that regulate the development of autoreactive B cells. The Mer receptor tyrosine kinase (Mertk) mediates apoptotic cell clearance and regulates cytokine production. Although Mertk was previously not believed to be expressed on B cells, we recently reported unresponsiveness of Mertk-/- B cells to class II-alloactivation in a chronic GVH model. In the present study, we show that B cells from Mertk-/- mice but not WT B6 mice exhibited a decreased but more sustained calcium influx when stimulated by MHC-II cross-linking, indicating an intrinsic B-cell defect. In addition, in cGVH induced with CD4+ T cells from bm12 mice into Rag-/- mice reconstituted with mixed chimeras with bone marrows from Mertk-/- mice and C20 mice, autoantibodies came only from wild type (a allotype) and not from Mertk-deficient (b allotype) B cells. Compared to wild type, MZB cells from Mertk-/- mice were unable to down regulate surface CD1d expression and subsequent inclusion in the MZ, correlating with significant lower germinal center (GC) responses assessed by absolute GC numbers and PNA staining. Taken together, these data show that Mertk is needed for class II-activation of B cells, and that Mertk plays a role in CD1d down-regulation on MZ B cells, a potential mechanism limiting B-cell activation in cGVH.