DEFECTIVE NEGATIVE REGULATION OF ANTIGEN RECEPTOR SIGNALING IN LYN-DEFICIENT B-LYMPHOCYTES

Background: To elucidate the role of the Src family kinase Lyn in B ce ll receptor (BCR) signaling, we and others previously generated lyn(-/ -)mice and analyzed their B cell responses. Although the initiation of BCR signaling in lyn(-/-)B cells is delayed, BCR-induced ERK2 activat ion and proliferation are enhanced, As the co-receptors Fc gamma RIIb1 and CD22 have been shown to be negative regulators of BCR signaling, we have now examined their functional roles in lyn(-/-)B cells. Result s: B cells from lyn(-/-)mice have increased expression of the protein product of the early response gene egr-1, enhanced activation of Jun N -terminal kinase (JNK), and elevated calcium responses upon BCR cross- linking. Tyrosine phosphorylation of Fc gamma RIIb1 in lyn(-/-)B cells was reduced but negative regulation of the BCR signal by Fc gamma RII b1 was only modestly impaired. In contrast, tyrosine phosphorylation o f CD22 was greatly decreased in lyn(-/-)B cells, correlating with the inability of CD22 to downregulate the BCR-induced calcium response in these cells. Surprisingly, CD22 remains capable of regulating the ERK2 and JNK pathways in lyn(-/-)B cells, which may relate to the small re sidual increase in BCR-induced CD22 phosphorylation. Conclusions: BCR signal initiation and negative regulation by Fc gamma RIIb1 is not cri tically dependent on Lyn. In contrast, Lyn plays a particularly import ant role in the tyrosine phosphorylation of CD22 and in the consequent inhibition of BCR-induced calcium influx. The net result of the Lyn d eficiency in B cells is hyperresponsiveness to antigen stimulation, wh ich may explain the autoimmunity observed in lyn(-/-)mice. (C) Current Biology Ltd ISSN 0960-9822.