TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

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.

Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

“…Although an immunodeficiency phenotype has not been reported for Tet2-KO mice, recent studies imply a crucial role for TET2 in maintaining T-cell homeostasis and B-cell development. 38,52,53 In agreement with the mouse KO model, in which TET2 deficiency and subsequent 5hmC reduction affected differentiation of T-cell subsets, 54 we detected relative loss of Th subsets (Tfh, Th1, and Th17), with a skew toward the Th2 fate and preservation of Treg numbers. Abnormal Treg proliferation and Foxp3 destabilization were observed only after double Tet2/Tet3-KO in mice.…”

TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

“…Expression of TET1 is drastically reduced in pro-B-cells (Cimmino et al, 2015 ), while expression of TET2 and TET3 increases progressively over B-cell maturation and during activation (Schoeler et al, 2019 ). Tet-mediated 5hmC accumulation in B-cells was shown to occur within gene bodies (Cimmino et al, 2015 ; Schoeler et al, 2019 ) and at enhancer regions (Lio et al, 2016 ; Orlanski et al, 2016 ), additionally correlating with H3K4me1 histone modifications and increased transcriptional activity (Lio et al, 2016 ; Orlanski et al, 2016 ). Loss of TET1 in hematopoietic stem cells promotes differentiation with a lymphoid bias (Cimmino et al, 2015 ).…”

“…TET2 and TET3 proteins regulate somatic hypermutation (SHM) and CSR through Tet-dependent upregulation of Activation Induced Deaminase (AID) in activated B-cells (Lio et al, 2019a ; Schoeler et al, 2019 ). These studies showed that TET proteins were recruited to two sites within the AID super-enhancer, TetE1 and TetE2 (Lio et al, 2019a ), by the basic leucine zipper transcription factor, ATF-like (BATF) (Lio et al, 2019a ; Schoeler et al, 2019 ).…”

Circles of Life: linking metabolic and epigenetic cycles to immunity

“…In B cells, loss of TET enzymes resulted in impaired class switch recombination, a process by which antibody switch from IgM to other isotypes. 61,67,88 Mechanistically, TET2 and TET3 cooperate with transcription factor Basic leucine zipper transcription factor (BATF) to promote the expression of activation-induced cytidine deaminase, the key enzyme for antibody maturation. 67 Tet2 deficiency resulted in increased germinal center B cells and decreased plasma cell differentiation after immunization.…”