Journal
FEBS JOURNAL
Volume 286, Issue 18, Pages 3566-3581Publisher
WILEY
DOI: 10.1111/febs.14934
Keywords
B cells; germinal centre; somatic hypermutation; TET2; TET3
Categories
Funding
- Austrian Cancer Aid [KH15017] Funding Source: Medline
- FWF-Funded Doctoral College 'Molecular Cell Biology and Oncology' [W1101] Funding Source: Medline
- Tyrolean Science Fund [UNI-0404/1696] Funding Source: Medline
- Austrian Academy of Sciences Funding Source: Medline
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available