Prolonged apoptotic cell accumulation in germinal centers of mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production

摘要

Mer receptor tyrosine kinase is a member of the Tyro-3/Axl/Mer (TAM) subfamily of receptor tyrosine kinases, and its expression on phagocytes facilitates their clearance of apoptotic cells (ACs). Mer expression in germinal centers (GCs) occurs predominantly on tingible body macrophages. B and T cells do not express Mer. In this study, we show that Mer deficiency ((Mer -/-) resulted in the long-term accumulation of ACs primarily in GCs and not in the T cell zone, marginal zone, or red pulp areas of the spleen. AC accumulation in GCs led to augmented Ab-forming cell, GC, and IgG2 Ab responses in Mer-/- mice, which were sustained for at least 80 d. Enhanced responses in Mer-/- mice were due to increased activation and proliferation of B cells and CD4+ Th cells, including follicular helper T cells, which resulted in high titers of anti-nuclear Abs in Mer -/- mice compared with wild-type controls. Secondary IgG-producing Ab-forming cell, total IgG, and IgG2 Ab responses were also increased in Mer-/- mice. Finally, compared with wild-type controls, Mer -/- mice had increased percentage of IFN-γ-producing CD4 + Th cells and elevated levels of Th1 (i.e., IL-2 and IFN-γ) and proinflammatory (i.e., TNF and IL-6) cytokines, consistent with elevated levels of Th1-biased IgG2 Abs in Mer-/- mice. Together, our results demonstrate that Mer deficiency induces prolonged accumulation of ACs in GCs, resulting in dysregulation of GC B cell and CD4+ Th cell responses and Th1 cytokine production, leading to alteration of B cell tolerance and the development of autoantibodies.