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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells
Author(s) -
Schoeler Katia,
Aufschnaiter Andreas,
Messner Simon,
Derudder Emmanuel,
Herzog Sebastian,
Villunger Andreas,
Rajewsky Klaus,
Labi Verena
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14934
Subject(s) - germinal center , cytidine deaminase , biology , activation induced (cytidine) deaminase , b cell , microbiology and biotechnology , immunoglobulin class switching , reprogramming , antibody , gene , genetics
Upon activation by antigen, B cells form germinal centres where they clonally expand and introduce affinity‐enhancing mutations into their B‐cell receptor genes. Somatic mutagenesis and class switch recombination (CSR) in germinal centre B cells are initiated by the activation‐induced cytidine deaminase ( AID ). Upon germinal centre exit, B cells differentiate into antibody‐secreting plasma cells. Germinal centre maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of ten‐eleven‐translocation ( 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 TET 2 and TET 3 guide the transition of germinal centre B cells to antibody‐secreting plasma cells. Optimal AID expression requires TET function, and TET 2 and TET 3 double‐deficient germinal centre B cells show defects in CSR. However, TET 2/ TET 3 double‐deficiency does not prevent the generation and selection of high‐affinity germinal centre B cells. Rather, combined TET 2 and TET 3 loss‐of‐function in germinal centre B cells favours C‐to‐T and G‐to‐A transition mutagenesis, a finding that may be of significance for understanding the aetiology of B‐cell lymphomas evolving in conditions of reduced TET function.