Transitional B cell fate is associated with developmental stage-specific regulation of diacylglycerol and calcium signaling upon B cell receptor engagement.
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.
Hoek
Kristen L
KL
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Antony
Pierre
P
Lowe
John
J
Shinners
Nicholas
N
Sarmah
Bhaskarjyoti
B
Wente
Susan R
SR
Wang
Demin
D
Gerstein
Rachel M
RM
Khan
Wasif N
WN
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*
D004075:Diglycerides; D011947:Receptors, Antigen, B-Cell