B cell systems that protect organisms from viral infection walk a fine line because the molecules they detect--such as unmethylated DNA--can also be derived from host cells, and an overzealous defense results in autoimmune disease. Chaturvedi et al. describe new insight into how components of the adaptive and innate immune systems--B cell receptors (BCRs) and Toll-like receptor 9 (TLR9), respectively--act together to sense DNA-containing antigens. The answer was not obvious because the BCR is thought to act primarily on the cell surface, whereas TLR9 is normally present on endocytic vesicles. The authors used confocal fluorescence microscopy and immunoelectron microscopy to show that in mouse B cells in which the BCR was activated, TLR9 was relocated into autophagosomes. When cells were stimulated just through TLR9 with unmethylated DNA, phosphorylated (thus, activated) p38 mitogen-activated protein kinase (MAPK) was detected only in endosomes. However, if the BCR was activated with an antibody to immunoglobulin M (IgM) (alone or with DNA to activate TLR9), p38 was detected in large autophagosome-like structures. The recruitment of TLR9 to this compartment appeared to depend on physical internalization of the BCR because treatment of cells with an inhibitor of BCR internalization that still allowed early signaling events prevented relocalization of TLR9. Pharmacological inhibition of phospholipase D (PLD) revealed that activation of the lipase in response to the BCR was necessary for the recruitment of TLR9 to the autophagosomes. In commentary, Monroe and Keir discuss how the cooperation of BCR and TLR appears to be spatially restricted to vesicles where TLRs can interact with unmethylated DNA in the antigen cargo carried by the BCR. They emphasize that the paper opens new areas for further exploration, including the spatial organization of signaling by immune receptors and the continued signaling of internalized BCR after its movement away from the plasma membrane.
A. Chaturvedi, D. Dorward, S. K. Pierce, The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity 28, 799-809 (2008). [PubMed]
J. G. Monroe, M. E. Keir, Bridging Toll-like- and B cell-receptor signaling: Meet me at the autophagosome. Immunity 28, 729-731 (2008). [PubMed]