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.

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SummaryCD4 T follicular helper (Tfh) cells are specialized in helping B cells during the germinal center (GC) reaction and ultimately promote long-term humoral immunity. Here we report that loss of the nuclear orphan receptor NR2F6 causes enhanced survival and accumulation of Tfh cells, GC B cells, and plasma cells (PCs) following T cell-dependent immunization. Nr2f6-deficient CD4 T cell dysfunction is the primary cause of cell accumulation. Cytokine expression in Nr2f6-deficient Tfh cells is dysregulated, and Il21 expression is enhanced. Mechanistically, NR2F6 binds directly to the interleukin 21 (IL-21) promoter and a conserved noncoding sequence (CNS) near the Il21 gene in resting CD4+ T cells. During Tfh cell differentiation, this direct NR2F6 DNA interaction is abolished. Enhanced Tfh cell accumulation in Nr2f6-deficient mice can be reverted by blocking IL-21R signaling. Thus, NR2F6 is a critical negative regulator of IL-21 cytokine production in Tfh cells and prevents excessive Tfh cell accumulation.