Abstract
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.
Highlights
Epigenetic regulation at the level of DNA is largely mediated by covalent addition of a methyl moiety at the 5th carbon of cytosines via DNA methyltransferases (DNMT) [1]. 5-methylcytosine (5mC), enriched in the context of CpG dinucleotides, associates with a local repression of gene expression [2]
The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
TET2 and TET3 are expressed throughout B-cell development and terminal differentiation
Summary
Epigenetic regulation at the level of DNA is largely mediated by covalent addition of a methyl moiety at the 5th carbon of cytosines via DNA methyltransferases (DNMT) [1]. 5-methylcytosine (5mC), enriched in the context of CpG dinucleotides, associates with a local repression of gene expression [2]. It has been assumed that the DNA methylation patterns that are Abbreviations 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; AID, activation-induced cytidine deaminase; BCR, B-cell antigen receptor; CB, centroblast; CC, centrocyte; CGG, chicken gammaglobulin; CSR, class switch recombination; DLBCL, Diffuse Large B-cell Lymphoma; DNMT, DNA methyltransferase; DZ, dark zone; FO, follicular; GC, germinal centre; iGC, induced germinal centre; LZ, light zone; MZ, marginal zone; NP, 4-hydroxy-3-nitrophenylacetyl; PC, plasma cell; RBC, red blood cell; SHM, somatic hypermutation; TET, ten-eleventranslocation. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies Mounting evidence suggests that context-dependent changes in DNA methylation may be functional during postnatal lineage priming, commitment and cell function [3,4,5,6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
