Impaired apoptotic cell clearance in the germinal center by Mer-deficient tingible body macrophages leads to enhanced antibody-forming cell and germinal center responses

摘要

Germinal centers (GC) are specialized microenvironments that generate high-affinity antibody-forming (AFCs) and memory B cells. Many B cells undergo apoptosis during B-cell clonal selection in GC. Although the factors that regulate the AFC and GC responses are not precisely understood, it is widely believed that dysregulated AFCs and GCs contribute to autoimmunity. The Mer receptor tyrosine kinase (MerTK or Mer) facilitates macrophage clearance of apoptotic cells. The TAM (Tyro-3, Axl, and Mer) receptors, including Mer, suppress Toll-like receptors (TLRs) and cytokine-mediated inflammatory responses. We report here that tingible body macrophages (TBMϕs) in GC express Mer. Compared to C57BL/6 (B6) controls, Mer deficient (Mer−/−) mice had significantly higher AFC, GC and Th1-skewed antibody (IgG2c) responses against the T-dependent Ag (4-hydroxy-3-nitrophenyl) acetyl (NP)-chicken gamma globulin (CGG). Mer−/− mice had significantly higher percentage of GC B cells on days 9, 14 and 21 post-immunization compared to B6 controls. Significantly increased numbers of apoptotic cells accumulated in Mer−/− GCs than in B6 GCs, while the number of TBMϕs remained similar in both strains. Our data are the first to demonstrate a critical role for Mer in GC apoptotic cell clearance by TBMϕs and have interesting implications for Mer in the regulation of B cell tolerance operative in the AFC and GC pathways.