The B cell receptor governs the subcellular location of Toll‐like receptor 9 leading to hyper‐responses to DNA‐containing antigens

Abstract

TLR9 plays a critical role in regulating auto-antibody production in response to DNA-containing antigens by mechanisms that involve synergistic signaling from simultaneously engaged TLR9 and B cell receptors (BCRs). However, the cellular and molecular basis of this critical 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 hyperresponses to DNA-containing antigens are achieved. When activated independently the BCR and TLR9 signal from discrete subcellular compartments, the BCR initially from the plasma membrane and later from intracellular compartments and TLR9 from endosomes. Remarkably, internalized BCR signals through a phospholipase D-dependent pathway to recruit TLR9-containing endosomes to the autophagosome-like compartments via the microtubular network. Moreover, recruitment of TLR9 to the autophagosome-like compartments is necessary for the B cell hyperresponses to DNA-containing antigens. Thus, the BCR and TLR9 that are spatially segregated in resting cells become colocalized in response to DNA-containing antigens. This novel pathway of BCR-induced TLR9 recruitment may provide new targets for therapeutic drug design for autoimmune diseases.