The Src-family kinase Lyn plays a critical role in establishing and maintaining B cell anergy by suppressing PI3K-dependent signaling.

Although the Src family kinase (SFK) Lyn is known to be involved in induction and maintenance of peripheral B cell tolerance, the molecular basis of its action in this context remains unclear. This question has been approached using conventional as well as B cell-targeted knockouts of Lyn, with varied conclusions likely confused by collateral loss of Lyn functions in B cell and myeloid cell development and activation. Here we utilized a system in which Lyn gene deletion is tamoxifen inducible and B cell restricted. This system allows acute elimination of Lyn in B cells without off-target effects. This genetic tool was employed in conjunction with immunoglobulin transgenic mice in which peripheral B cells are autoreactive. DNA reactive Ars/A1 B cells require continuous inhibitory signaling, mediated by the inositol phosphatase SHIP-1 and the tyrosine phosphatase SHP-1, to maintain an unresponsive (anergic) state. Here we show that Ars/A1 B cells require Lyn to establish and maintain B cell unresponsiveness. Lyn primarily functions by restricting PI3K-dependent signaling pathways. This Lyn-dependent mechanism complements the impact of reduced mIgM BCR expression to restrict BCR signaling in Ars/A1 B cells. Our findings suggest that a subset of autoreactive B cells requires Lyn to become anergic and that the autoimmunity associated with dysregulated Lyn function may, in part, be due to an inability of these autoreactive B cells to become tolerized.