Effects of apoptotic cell accumulation caused by Mer deficiency on germinal center B cells and follicular helper T cells (171.12)

Abstract

Abstract Mer (MerTK) is a member of the Tyro-3/Axl/Mer (TAM) subfamily receptor tyrosine kinases which facilitates phagocyte clearance of apoptotic cells (ACs). We previously showed that Mer expression in germinal centers (GCs) occurs predominantly on tingible body macrophages (TBMϕs). Furthermore, deficiency in Mer (Mer-/-) results in accumulation of ACs in GCs leading to augmented antibody-forming cell (AFC), GC and Th1-skewed IgG2 Ab responses. Here we show that elevated AFC, GC and IgG2 Ab responses in Mer-/- mice were due to increased proliferation of B cells and higher number of TFH cells in Mer-/- GCs. AC accumulation in Mer-/- GCs was also associated with elevated long-lived primary and secondary AFC, GC B cell, TFH cell and IgG2 Ab responses compared to controls. Interestingly, AC accumulation in Mer-/- GCs was not due to increased B cell apoptosis, rather due to a defect in AC clearance. Finally, by evaluating GC TBMϕ expression of several other bridging molecules and receptors (i.e., Axl, Tyro-3, Mfge-8 and Tim-4) involved in AC clearance, we ruled out the contribution of the potential alteration in the expression of these molecules/receptors to AC accumulation in Mer-/- GCs. These data indicate that accumulation of ACs in Mer-/- GCs is primarily due to Mer deficiency. Together these results highlight the important role of AC clearance by Mer in regulating GC B cell and TFH cell responses and in maintaining peripheral B cell tolerance.