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CD72 Down-Modulates BCR-Induced Signal Transduction and Diminishes Survival in Primary Mature B Lymphocytes¹

Daniel H. Li^*, James W. Tung, Ingo H. Tarner^*,, Andrew L. Snow, Tsuyoshi Yukinari^*, Rachel Ngernmaneepothong^*, Olivia M. Martinez and Jane R. Parnes^2,*

^* Division of Immunology and Rheumatology, Department of Medicine, Department of Genetics, and Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; and Justus Liebig University Giessen, Department of Internal Medicine, Rheumatology, and Clinical Immunology, Division of Rheumatology and Clinical Immunology, Kerckhoff-Klinik Bad Nauheim, Bad Nauheim, Germany

CD72, a 45-kDa type II transmembrane glycoprotein carrying an ITIM motif, is believed to be an inhibitory coreceptor of the BCR. Mature B cells lacking CD72 show enhanced Ca²⁺ mobilization and are hyperproliferative in response to BCR ligation. However, the signal transduction pathways downstream of BCR signaling that transmit the inhibitory effect of CD72 in mature B cells remain unknown. To address this question, we used hen egg lysozyme-specific BCR transgenic mice to elucidate the differential cell signaling between wild-type and CD72-deficient B cells in response to hen egg lysozyme Ag stimulation. Our results demonstrate that CD72 predominantly down-regulates the major signal transduction pathways downstream of the BCR, including NF-AT, NF-B, ERK, JNK, p38-MAPK, and PI3K/Akt in mature B cells. CD72 ligation with anti-CD72 Ab (K10.6), which mimics the binding of CD100 (a natural ligand for CD72) to release the inhibitory function of CD72, augments cell proliferation, Ca²⁺ flux, IB activation, and ERK MAPK activity upon Ag stimulation in wild-type B cells. In addition, we show direct evidence that CD72 promotes cell cycle arrest and apoptosis after Ag stimulation in mature B cells. Taken together, our findings conclude that CD72 plays a dominant role as a negative regulator of BCR signaling in primary mature B lymphocytes.

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