Lyn governs the establishment and maintenance of B cell anergy by suppressing PI3K signaling.

The Src family kinase Lyn is known to be involved in the induction and maintenance of peripheral B cell tolerance; however, mechanistic separation of tolerogenic functions from the role of Lyn in B cell and myeloid cell development and activation is challenging. Here we utilize a system in which Lyn deletion is tamoxifen inducible and B cell restricted, which allows acute elimination of Lyn in B cells only, minimizing confounding factors. This genetic tool is 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 via restricting PI3K-dependent signaling pathways. This Lyn-dependent mechanism complements the impact of reduced mIgM B cell receptor (BCR) expression to restrict BCR signaling in Ars/A1 B cells. Our findings thus 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.