Regulatory mechanism on B cell antigen receptor-mediated signal transduction and gene expression.

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B cell antigen receptor (BCR)-mediated signals play a crucial role in determination and regulation of B cell differentiation or apoptotic cell death. In the present study, we focus on the roles of Lyn kinase and phosphatidylinositol signal pathway in regulation of B1 cell activation. Mice obtained from crossing Lyn kinase-deficient mice with transgenic mice carrying heavy and light chain genes encoding for autoantibody to erythrocytes showed abnormal increase and maturation of B1 cells. We found that signals from co-stimulatory receptors such as CD5, CD72 and FcγRIIB play as crucial negative regulators for BCR-mediated signal transduction. These receptors possess ITIM motif on cytoplasmic tail. We found Lyn kinase is an essential kinase for tyrosine phosphorylation of those ITIM, to which SHP-1 recruits rapidly. Recruitment of SHP-1 shut off BCR-mediated signals by de-phosphorylation. Therefore, B1 cells show minimum response against BCR-mediated antigen stimulation. Lyn kinase is thus obligatory for the SHP-1 recruitment to the phosphorylated ITIM on CD5, CD73 and FcγRIIB.The transgenic mice carrying heavy and light chain genes encoding for autoantibody to erythrocytes did not develop hemolytic anemia because of those strong negative regulation. Lack of Lyn kinase, however, eliminated these negative regulation. Lyn-negative transgenic mice thus developed autoimmune hemolytic anemia. Furthermore, we found another co-receptor that showed negative regulation for BCR-mediated signaling. It is Ly49. The Ly49 is known as a negative regulator on NK cells, which binds to MHC class I.Ly49 was detected on B1 cells but not on B2 cells. Throsine phosphorylation of Ly49 was induced by Lyn kinase and SHP-1 recruits to the phosphorylated Ly49. These results clearly indicated that Lyn kinase plays an essential role in negative regulation of autoreactive B1 cells and prevention of autoantibody production.