B cell receptor signaling governs the subcellular location of Toll-like receptor 9 (86.11)

Abstract

Abstract Toll-like receptor 9 (TLR9), an innate immune system receptor for hypomethylated CpG DNA motifs, has gained substantial attention recently due to its unique ability to promote the activation of autoreactive B cells in response to DNA-containing antigens. Many of the autoantigens targeted in systemic lupus erythematosus (SLE) contain DNA. Moreover, TLR9 has been shown to play a critical role in regulating anti-DNA autoantibody production in mouse models of lupus by mechanisms that involve the simultaneous engagement of TLR9 and the B cell receptor (BCR). However, the cellular and molecular basis of the interaction between TLR9 and the BCR is not known and given the spatial segregation of the BCR on the plasma membrane and TLR9 in early endosomal compartments, it is not obvious how synergy is achieved. Here we show that when activated independently the BCR and TLR9 signal from discrete subcellular compartments, the BCR initially from the plasma membrane and later from large multivesicular bodies (MVB) and TLR9 from multiple endosomes. Remarkably, stimulation of B cells simultaneously through the BCR and TLR9 triggers the recruitment of the TLR9-containing endosomes to the MVB by a Src-family kinase-dependent, MyD88-independent mechanism resulting in a synergistic response. Thus, the BCR triggers the recruitment of TLR9- containing vesicles to the MVB presumably to allow TLR9 to survey the BCR bound antigen for its DNA ligand, which if present, results in TLR9 activation and enhanced B cell responses. Our study adds a new spatial dimension to our view of TLR9 signaling in the B cells, potentially providing a new arena for therapeutic drug design.