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

• Published in: Journal of Immunology Vol. 177; no. 8; pp. 5405 - 5413
• Main Authors: Hoek, Kristen L, Antony, Pierre, Lowe, John, Shinners, Nicholas, Sarmah, Bhaskarjyoti, Wente, Susan R, Wang, Demin, Gerstein, Rachel M, Khan, Wasif N
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.10.2006
• Subjects: Animals; B-Lymphocytes - cytology; Calcium Signaling - physiology; Cell Differentiation; Cell Survival; Diglycerides - physiology; Lymphocyte Subsets - cytology; Mice; Mice, Knockout; Phenotype; Receptors, Antigen, B-Cell - metabolism; Signal Transduction - physiology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.8.5405

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-gamma2, 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.