Lyn restrains lupus via kinase-independent mechanisms that limit Toll-like receptor activation and type I interferon responsiveness.

Abstract

Lyn phosphorylates inhibitory immunoreceptors to terminate signaling; consequently, Lyn deficiency in mice causes hyperactive immune cells and lupus-like autoimmune disease. Lyn may also suppress autoimmunity independent of its kinase activity through inhibitory protein-protein binding interactions, although the importance of this mechanism is unclear. To analyze the kinase-independent functions of Lyn, mice expressing a catalytically inactive mutant of Lyn were generated and their phenotype compared to Lyn-deficient mice. Disease progression was blunted in Lyn kinase-dead mice indicating a contribution for kinase-independent Lyn functions in restraining autoantibody production, glomerulonephritis, Toll-like receptor signaling, and splenomegaly. Further comparative analyses identified an exclusive role for the kinase-dependent functions of Lyn in regulating B cell receptor signaling, dendritic cell phenotype, and type I interferon production. By contrast, interferon-stimulated gene expression and the regulation of thymic epithelial cell development and T cell selection are previously unidentified, exclusively kinase-independent functions for Lyn. Collectively, these findings further our understanding of the nuanced roles of Lyn in health and disease.