title: Transitional B cell fate is associated with developmental stage-specific regulation of diacylglycerol and calcium signaling upon B cell receptor engagement.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Hoek
authors.forename: Pierre
authors.initials: P
authors.lastname: Antony
authors.forename: John
authors.initials: J
authors.lastname: Lowe
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shinners
authors.forename: Bhaskarjyoti
authors.initials: B
authors.lastname: Sarmah
authors.forename: Susan R
authors.initials: SR
authors.lastname: Wente
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gerstein
authors.forename: Wasif N
authors.initials: WN
authors.lastname: Khan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation; D002470:Cell Survival; D004075:Diglycerides / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004075:Diglycerides; D011947:Receptors, Antigen, B-Cell