Impaired Apoptotic Cell Clearance in the Germinal Center by Mer-Deficient Tingible Body Macrophages Leads to Enhanced Antibody-Forming Cell and Germinal Center Responses

Abstract

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.

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

“…Homozygous deletion of MERTK results in systemic autoimmunity from the failure to clear ACs by myeloid cells in peripheral tissues as well as defects in the post-partum mammary gland involution by failure to clear ACs by mammary epithelial cells (5,7,21,23,26). Given the strong phenotype of MERTK deficiency in primary mammary epithelial cells, in combination with the fact that MERTK is frequently overexpressed in mammary carcinoma (44 -46), we set out to study the effects of MERTK when overexpressed in mammary epithelial cells.…”

“…Although the single knock-out of mouse Mertk(Ϫ/Ϫ) has a milder phenotype, it recapitulates much of the biology of the triple knock-out with respect to autoimmunity, as tingible body macrophages in germinal centers from Mertk(Ϫ/Ϫ) mice are defective to clear ACs leading to autoantibody production (21)(22)(23). Mertk(Ϫ/Ϫ) mice also develop age-dependent blindness, abnormal spermatogenesis and infertility in males, and impaired clearance of ACs in the postpartum involuting mammary glands (24 -26).…”

Tim4- and MerTK-Mediated Engulfment of Apoptotic Cells by Mouse Resident Peritoneal Macrophages

“…Requirement of MerTK for the engulfment of apoptotic cells by tingible-body macrophages and thymic macrophages has been previously reported (35,45). Whether Tim4 or other Tim family members are required for the engulfment of apoptotic cells in these and other macrophage populations remains to be determined.…”

Impaired clearance of apoptotic cells in germinal centers: implications for loss of B cell tolerance and induction of autoimmunity

“…Even though both DCs and macrophages have been implicated in AC clearance, the phagocytes primarily mobilized into the GCs to efficiently clear ACs are a subset of macrophages named tingible body macrophages (TBMus, #7, Fig. 1) [32][33][34][35].…”