A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficientmice

CD19 and the Src family protein tyrosine kinases (PTKs) are important regul ators of intrinsic signaling thresholds in B cells. Regulation is achieved by cross-talk between Src family PTKs and CD19; Lyn is essential for CD19 p hosphorylation, while CD19 establishes an Src family PTK activation loop th at amplifies kinase activity. However, CD19-deficient (CD19(-/-)) B cells a re hyporesponsive to transmembrane signals, while Lyn-deficient (Lyn(-/-)) B cells exhibit a hyper-responsive phenotype resulting in autoimmunity. To identify the outcome of interactions between CD19 and Src family PTKs in vi vo, B cell function was examined in mice deficient for CD19 and Lyn (CD19/L yn(-/-)). Remarkably, CD19 deficiency suppressed the hyper-responsive pheno type of Lyn(-/-) B cells and autoimmunity characterized by serum autoantibo dies and immune complex-mediated glomerulonephritis in Lyn(-/-) mice. Consi stent with Lyn and CD19 each regulating conventional B cell development, BI cell development was markedly reduced by Lyn deficiency, with further redu ctions in the absence of CD19 expression. Tyrosine phosphorylation of Fyn a nd other cellular proteins induced following B cell Ag receptor ligation wa s dramatically reduced in CD19/Lyn(-/-) B cells relative to Lyn(-/-) B cell s, while Syk phosphorylation was normal. In addition, the enhanced intracel lular Ca2+ responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression. BCR-induced prolife ration and Immoral immune responses were also markedly inhibited by CD19/Ly n deficiency. These findings demonstrate that while the CD19/Lyn amplificat ion loop is a major regulator of signal transduction thresholds in B lympho cytes, CD19 regulation of other Src family PTKs also influences B cell func tion and the development of autoimmunity.