title: A role for Bcl6 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21.
abstract: IgE plays an important role in the pathogenesis of allergic diseases and high-affinity IgE memory B cells are differentiated from IgG1 B cells developed in germinal centers. Bcl6, a sequence specific transcriptional repressor, is highly expressed in germinal center B cells and suppresses expression of Cvarepsilon germline transcript. However, a role for Bcl6 in inhibition of the sequential class switching from IgG1 to IgE in germinal center B cells is not known. When splenic B cells from Bcl6-deficient (Bcl6-KO) and Bcl6-transgenic (Bcl6-TG) mice were stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4, IgG1(+)IgE(+) B cells were detected in Bcl6-KO B cell culture but not in Bcl6-TG B cell culture. Cgamma1 and Cvarepsilon germline transcript in Bcl6-KO B cells were induced earlier than those in wild-type (Bcl6-WT) B cells after stimulation. When activated B cells were simultaneously stimulated with IL-21, expression of Cgamma1 germline transcript in Bcl6-WT and Bcl6-KO B cells was enhanced by IL-21 stimulation, indicating that IL-21 is an enhancer of Cgamma1 expression induced by IL-4. The amount of Cgamma1 germline transcript in the Bcl6-KO B cells was more than that in the Bcl6-WT B cells. Conversely, IL-21 stimulation suppressed Cvarepsilon expression in the Bcl6-WT B cells. However, the suppression was not observed in the Bcl6-KO B cells, suggesting that the IL-21-mediated suppression of Cvarepsilon expression is due to Bcl6. Thus, Bcl6 controls the Cgamma1 and Cvarepsilon expression and stabilizes class switching to IgG1 in activated B cells simultaneously stimulated with IL-4 and IL-21.
authors.affiliation: Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitayama
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Arima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000502:physiology; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E; D050440:Immunoglobulin Subunits; D015847:Interleukin-4 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6; D000098546:Interleukin-21
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D050440:Immunoglobulin Subunits; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D015847:Interleukin-4; D007073:Immunoglobulin E; D000098546:Interleukin-21