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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

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Item Type:Article
Title:TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells
Creators Name:Schoeler, K. and Aufschnaiter, A. and Messner, S. and Derudder, E. and Herzog, S. and Villunger, A. and Rajewsky, K. and Labi, V.
Abstract:Upon activation by antigen, B cells form germinal centers where they clonally expand and introduce affinity-enhancing mutations into their B cell receptor genes. Somatic mutagenesis and class switch recombination in germinal center B cells are initiated by the activation-induced cytidine deaminase (AID). Upon germinal center exit, B cells differentiate into antibody-secreting plasma cells. Germinal center maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of TET proteins, enzymes that facilitate DNA demethylation and promote a permissive chromatin state by oxidizing 5-methylcytosine, in antibody-mediated immunity. Using a conditional gene ablation strategy, we show that TET2 and TET3 guide the transition of germinal center B cells to antibody-secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double-deficient germinal center B cells show defects in class switch recombination. However, TET2/TET3 double-deficiency does not prevent the generation and selection of high-affinity germinal center B cells. Rather, combined TET2 and TET3 loss-of-function in germinal center B cells favors C-to-T and G-to-A transition mutagenesis, a finding that may be of significance for understanding the etiology of B cell lymphomas evolving in conditions of reduced TET function.
Keywords:B Cells, Germinal Center, Somatic Hypermutation, TET2, TET3, Animals, Mice
Source:FEBS Journal
Page Range:3566-3581
Date:September 2019
Official Publication:https://doi.org/10.1111/febs.14934
PubMed:View item in PubMed

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