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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., Aufschnaiter, A., Messner, S., Derudder, E., Herzog, S., Villunger, A., 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 |
| ISSN: | 1742-464X |
| Publisher: | Wiley |
| Volume: | 286 |
| Number: | 18 |
| 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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