In:
The FEBS Journal, Wiley, Vol. 286, No. 18 ( 2019-09), p. 3566-3581
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 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.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/febs.v286.18
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2172518-4
SSG:
12
