Mer receptor tyrosine kinase signaling prevents TLR-mediated self-ligand sensing and aberrant selection in germinal centers

Abstract

Abstract Mer receptor tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells and inducing immunoregulatory signaling cascades. We previously showed that Mer-deficient mice on a mixed B6 and 129 background (B6129F2.Mer−/−) have increased germinal center (GC) responses, T cell activation, and apoptotic cell accumulation within GCs. Whereas B6129F2.Mer−/− mice accumulate apoptotic cells in GCs, B6.Mer−/− mice do not accumulate apoptotic cells, resembling B6 mice. Therefore, we used these two models to mechanistically separate the effects of debris released from secondary necrotic cells as a result of apoptotic cell accumulation from those driven by the loss of immune regulation by Mer. Through the study of global and cell-type intrinsic TLR and MyD88 deficiency in B6129F2.Mer−/− mice, we found that GC B cell-intrinsic sensing of self-RNA, but not self-DNA, released from secondary necrotic cells drives self-antigen induced GC responses. While self-ligands drive the magnitude of GC response, the loss of Mer immunoregulatory signaling bolsters antigen presentation and APC-intrinsic TLR activation drives pro-inflammatory cytokine production. Further, the loss of Mer immunoregulatory signaling accelerates the onset of autoimmunity when B6.Mer−/− mice are crossed to autoimmune-prone B6.Sle1b mice (Sle1b.Mer−/−) due to the retention of autoreactive B cells in GCs. Collectively, Mer prevents the cell-intrinsic activation of GC B cells and APCs to regulate the magnitude of GC response and T cell activation, in addition to regulating GC selection events to prevent the development of autoimmunity.