Sirt1 modulates immunoglobulin class switch DNA recombination and somatic hypermutation by regulating B lymphocyte Aicda expression through NF-kB deacetylation

Abstract

Abstract Maturation of the antibody response entails Ig class switch DNA recombination (CSR) and somatic hypermutation (SHM), which perfect the antigen-binding activity and diversify the effector functions of antibodies. By showing that HDAC inhibitors selective for class I/II HDACs dampened CSR and SHM by downregulating AID through upregulation of selected microRNAs that target Aicda, we have outlined an important role of these Zn-dependent HADCs in the modulation of the antibody response. Here we showed that Sirt1, one of the NAD+-dependent Class III HDACs or Sirtuins, also plays an important role in the regulation of B cell CSR and SHM. Sirt1 deletion in AID-expressing B cells of AicdacreSirt1fl/fl mice, whose B cells contain the normal complement of Aicda genes together with a Cre gene under control of an extra Aicda promoter, led to increased class-switched and somatically mutated antibodies in response to NP-CGG, as a result of upregulated AID expression, without alteration of Prdm1 expression or plasma cell differentiation. Sirt1-deficient B cells hyperacetylated p65, thereby activating the canonical NF-kB pathway, which mediates Aicda activation, without changes in DNA methylation or histone acetylation of the Aicda promoter. This was mimicked by increased concentrations of glucose, which reduced the NAD+ Sirt1 co-factor, leading to p65 hyperacetylation and Aicda upregulation in B cells. Conversely, treatment of B cells with NAD+ or SRT1720, a potent Sirt1 activator, dampened Aicda expression. Thus, our findings outline an important B cell-intrinsic role of Sirt1 in the modulation of the antibody response.