title: B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2.
abstract: Signaling from the BCR and B cell activating factor receptor (BAFF-R or BR3) differentially regulates apoptosis within early transitional (T1) and late transitional (T2; CD21(int)-T2) B cells during selection processes to generate mature B lymphocytes. However, molecular mechanisms underlying the differential sensitivity of transitional B cells to apoptosis remain unclear. In this study, we demonstrate that BCR signaling induced more long-term c-Rel activation in T2 and mature than in T1 B cells leading to increased expression of anti-apoptotic genes as well as prosurvival BAFF-R and its downstream substrate p100 (NF-kappaB2). Sustained c-Rel activation required de novo c-Rel gene transcription and translation via Btk-dependent mechanisms. Like T1 cells, mature B cells from Btk- and c-Rel-deficient mice also failed to activate these genes. These findings suggest that the gain of survival potential within transitional B cells is dependent on the ability to produce a long-term c-Rel response, which plays a critical role in T2 B cell survival and differentiation in vivo by inducing anti-apoptotic genes, BAFF-R and NF-kappaB2, an essential component for BAFF-R survival signaling. Thus, acquisition of resistance to apoptosis during transitional B cell maturation is achieved by integration of BCR and BAFF-R signals.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Castro
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wright
authors.forename: Bazarragchaa
authors.initials: B
authors.lastname: Damdinsuren
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Hoek
authors.forename: Gianluca
authors.initials: G
authors.lastname: Carlesso
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Shinners
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gerstein
authors.forename: Robert T
authors.initials: RT
authors.lastname: Woodland
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
authors.forename: Wasif N
authors.initials: WN
authors.lastname: Khan
mesh_terms: D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D053265:B-Cell Activation Factor Receptor; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel; D011947:Receptors, Antigen, B-Cell