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*
Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
CD19 and the Src family protein tyrosine kinases (PTKs) are important regulators of intrinsic signaling thresholds in B cells. Regulation is achieved by cross-talk between Src family PTKs and CD19; Lyn is essential for CD19 phosphorylation, while CD19 establishes an Src family PTK activation loop that amplifies kinase activity. However, CD19-deficient (CD19-/-) B cells are 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 vivo, B cell function was examined in mice deficient for CD19 and Lyn (CD19/Lyn-/-). Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn-/- B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn-/- mice. Consistent with Lyn and CD19 each regulating conventional B cell development, B1 cell development was markedly reduced by Lyn deficiency, with further reductions in the absence of CD19 expression. Tyrosine phosphorylation of Fyn and other cellular proteins induced following B cell Ag receptor ligation was dramatically reduced in CD19/Lyn-/- B cells relative to Lyn-/- B cells, while Syk phosphorylation was normal. In addition, the enhanced intracellular Ca2+ responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression. BCR-induced proliferation and humoral immune responses were also markedly inhibited by CD19/Lyn deficiency. These findings demonstrate that while the CD19/Lyn amplification loop is a major regulator of signal transduction thresholds in B lymphocytes, CD19 regulation of other Src family PTKs also influences B cell function and the development of autoimmunity.
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