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

FEBS J. 2019 Sep;286(18):3566-3581. doi: 10.1111/febs.14934. Epub 2019 Jun 3.


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 TET2 and TET3 guide the transition of germinal centre B cells to antibody-secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double-deficient germinal centre B cells show defects in CSR. However, TET2/TET3 double-deficiency does not prevent the generation and selection of high-affinity germinal centre B cells. Rather, combined TET2 and TET3 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.

Keywords: B cells; TET2; TET3; germinal centre; somatic hypermutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism
  • Animals
  • Antibody Formation / genetics
  • Antibody Formation / immunology
  • Antibody-Producing Cells / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Chromatin / genetics
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • DNA Demethylation
  • DNA Methylation / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Dioxygenases / genetics*
  • Dioxygenases / immunology
  • Gene Expression Regulation / immunology
  • Germinal Center / immunology
  • Humans
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Class Switching / immunology
  • Mice
  • Mutation / genetics
  • Mutation / immunology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / immunology


  • Chromatin
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • 5-Methylcytosine
  • Dioxygenases
  • Tet2 protein, mouse
  • Tet3 protein, mouse
  • Cytidine Deaminase