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Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement¹

Kristen L. Hoek^2,*, Pierre Antony^2,*, John Lowe^*, Nicholas Shinners^*, Bhaskarjyoti Sarmah, Susan R. Wente, Demin Wang^,, Rachel M. Gerstein^¶ and Wasif N. Khan^3,*

^* Department of Microbiology and Immunology, and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; The Blood Research Institute, Blood Center of Wisconsin, and Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and ^¶ Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655

Functional peripheral mature follicular B (FoB) lymphocytes are thought to develop from immature transitional cells in a BCR-dependent manner. We have previously shown that BCR cross-linking in vitro results in death of early transitional (T1) B cells, whereas late transitional (T2) B cells survive and display phenotypic characteristics of mature FoB cells. We now demonstrate that diacylglycerol (DAG), a lipid second messenger implicated in cell survival and differentiation, is produced preferentially in T2 compared with T1 B cells upon BCR cross-linking. Consistently, inositol 1,4,5-triphosphate is also produced preferentially in T2 compared with T1 B cells. Unexpectedly, the initial calcium peak appears similar in both T1 and T2 B cells, whereas sustained calcium levels are higher in T1 B cells. Pretreatment with 2-aminoethoxydiphenylborate, an inhibitor of inositol 1,4,5-triphosphate receptor-mediated calcium release, and verapamil, an inhibitor of L-type calcium channels, preferentially affects T1 B cells, suggesting that distinct mechanisms regulate calcium mobilization in each of the two transitional B cell subsets. Finally, BCR-mediated DAG production is dependent upon Bruton’s tyrosine kinase and phospholipase C-2, enzymes required for the development of FoB from T2 B cells. These results suggest that calcium signaling in the absence of DAG-mediated signals may lead to T1 B cell tolerance, whereas the combined action of DAG and calcium signaling is necessary for survival and differentiation of T2 into mature FoB lymphocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by National Institutes of Health Grant RO1 GM51219 (to S.R.W.); National Institutes of Health Grant R01 HL073284 and American Cancer Society Grant RSG CCG-106204 (to D.W.); National Institutes of Health Grant RO1 AI043534 (to R.M.G.); National Institutes of Health Grants RO1 AI50213-01 and AI060729-01 and American Cancer Society Grant RSG TBE-102299 (to W.N.K.); and National Institutes of Health Grant P01 HL68744-01 (to W.N.K.). K.L.H. and N.S. were supported by National Institutes of Health Grant T32 HL69715.

² K.L.H. and P.A. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Wasif N. Khan, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue South, A4207 Medical Center North, Nashville, TN 37232-0146. E-mail address: wasif.khan{at}vanderbilt.edu

⁴ Abbreviations used in this paper: Fo, follicular; MZ, marginal zone; HSA, heat-stable Ag; BTK, Bruton’s tyrosine kinase; PKC, protein kinase C; PLC, phospholipase C; PIP₂, phosphatidylinositol-4,5-bisphosphate; IP₃, inositol 1,4,5-triphosphate; FCM, flow cytometry; IP, immunoprecipitation; 2-APB, 2-aminoethoxydipheylborate.

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