Sirt1-mediated metabolic modulation of Aicda, class-switch DNA recombination and somatic hypermutation

Abstract

Abstract Maturation of the antibody response entails Ig somatic hypermutation (SHM) and class switch DNA recombination (CSR). SHM and CSR perfect the antigen-binding activity and diversify the effector functions of antibodies. By showing that histone deacetylase (HDAC) inhibitors selective for class I/II HDACs dampened SHM/CSR by decreasing activation induced cytidine deaminase (AID) expression through upregulation of miRNAs that target Aicda, we have outlined an important role of Zn-dependent HDACs in the modulation of the antibody response. Here we have shown that the NAD+-dependent Class III HDAC Sirt1 also plays an important role in the regulation of SHM and CSR. B cells undergoing CSR/SHM profoundly downregulated Sirt1. Sirt1 deletion in AID-expressing B cells of AicdacreSirt1fl/fl mice, led to increased CSR and SHM in response to NP-CGG, as a result of upregulated AID expression, without altering Prdm1 expression. Sirt1-deficient B cells reduced DNA methylation in the Aicda promoter and hyperacetylated p65, thus activating the canonical NF-kB pathway, which mediates Aicda activation, in absence of any change in DNA methylation of the Prdm1 promoter or histone acetylation of the Aicda or Prdm1 promoter. Increased glucose concentration, which reduced NAD+ Sirt1 co-factor, led to hyperacetylated p65 and Aicda upregulation. Conversely, the NAD+ Sirt1 co-factor or SRT1720 small molecule, a specific Sirt1 activator, dampened Aicda expression and CSR once added to B cells. Thus, our findings outline an important B cell-intrinsic role of Sirt1 in the modulation of the antibody response. Such a role is independent from and may be in addition to the histone deacetylation activity of this Class III HDAC in immune cells other than B lymphocytes.