| Description |
Recently it has become clear that B cells in addition to the B cell receptors (BCR) also express a variety of innate immune receptors. Of particular interests are toll like receptors (TLRs) that recognize conserved pathogen associated molecular patterns (PAMPs). Signals through the TLRs, including TLR9 that recognizes hypo-methylated CpG-DNA motifs markedly influence the outcome of antigen engagement by the BCR. We provided evidence for a novel pathway by which the BCR regulates responses to DNA- containing antigens by controlling the subcellular location of TLR9. Following BCR crosslinking TLR9 is recruited from early endosomal to autophagosome-like compartments into which the BCR is internalized and where synergistic signaling to MAP kinase activation between BCR and TLR9 occurs. The observation that BCR endocytosis is required for crosstalk between the BCR and TLR9 suggested that BCR signaling continues from the intracellular compartment with the sequential recruitment and phosphorylation of kinases. Blocking BCR internalization results in the recruitment of both proximal and downstream kinases to the plasma membrane where they were either hyper- or hypo-phosphorylated resulting in dysregulation of activation-induced transcription. Collectively these studies enhance our understanding of how dysregulation of BCR-TLR interaction results in autoimmunity and tumorigenesis.
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