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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents

ID: 717300.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Suboptimal B-cell antigen receptor signaling activity in vivo elicits germinal center counterselection mechanisms
Authors:Konigsberger, S.; Weis, V.; Prodohl, J.; Stehling, M.; Hobeika, E.; Reth, M.; Kiefer, F.
Date of Publication (YYYY-MM-DD):2015-02
Title of Journal:European Journal of Immunology
Issue / Number:2
Start Page:603
End Page:611
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Syk and Zap-70 constitute a closely related nonreceptor protein tyrosine kinase family, of which both members are functionally indispensable for conferring their respective antigen receptors with enzymatic activity. In this study, we analyze the impact of altering BCR signaling output on B-cell germinal center (GC) fate selection by constitutive, as well as inducible, monoallelic Syk kinase loss in the presence of a Zap-70 knock-in rescue allele. Cre-mediated Syk deletion in Syk(flox/Zap-70) B cells lowers pErk, but not pAkt-mediated signaling. Surprisingly, the use of a B-cell-specific constitutive mb1-cre deleter mouse model showed that a small cohort of peripheral Syk(flox/Zap-70);mb1-cre B cells efficiently circumvents deletion, which ultimately favors these Syk-sufficient cells to contribute to the GC reaction. Using a developmentally unbiased Syk(flox/Zap-70);mb1-creER(T2) approach in combination with an inducible tdRFP allele, we further demonstrate that this monoallelic deletion escape is not fully explained by leakiness of Cre expression, but is possibly the result of differential Syk locus accessibility in maturing B cells. Altogether, this underscores the importance of proper Syk kinase function not only during central and peripheral selection processes, but also during GC formation and maintenance.
Free Keywords:Alleles; Animals; B-Lymphocytes/cytology/immunology/*metabolism; Extracellular Signal-Regulated MAP Kinases/genetics/immunology/metabolism; Gene Expression Regulation; Genetic Complementation Test; Germinal Center/cytology/immunology/*metabolism; Integrases/genetics/metabolism; Intracellular Signaling Peptides and Proteins/genetics/immunology/*metabolism; Mice; Mice, Transgenic; Phosphorylation; Protein-Tyrosine Kinases/genetics/immunology/*metabolism; Proto-Oncogene Proteins c-akt/genetics/immunology/metabolism; Receptors, Antigen, B-Cell/genetics/immunology/*metabolism; Signal Transduction; ZAP-70 Protein-Tyrosine Kinase/genetics/immunology/*metabolism; Bcr; Gc; Interclonal competition; Syk; Zap-70
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:%W NLM %G eng
Identifiers:ISSN:0014-2980 %R 10.1002/eji.201444538 [ID No:1]
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