Higher‐order CpG‐DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice

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Abstract
Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single‐stranded CpG‐oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG‐ODN capable of forming higher‐order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell‐activating factor, or simultaneous co‐engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF‐1, IL‐6 and IL‐12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self‐derived hypomethylated double‐stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co‐engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9‐induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.