Sirt1 modulates AID expression, class switch DNA recombination and somatic hypermutation by repressing NF-kB activity

Abstract

Abstract As we have suggested, epigenetic factors, such as histone deacetylases (HDACs), play critical roles in modulating the maturation of the antibody response. This entails class switch DNA recombination (CSR) and somatic hypermutation (SHM). CSR and SHM require AID and diversify the specificity and effector functions of antibodies. By showing that HDAC inhibitors (HDIs) that selectively block Classes I/II HDACs (the “classical” Zn-dependent HDACs together with Class IV HDAC), impaired AID and Blimp1 expression, CSR, SHM and plasma cell differentiation, we have previously outlined an important role of these Zn-dependent HADCs in the modulation of antibody response. We found that Sirt1, one of the NAD+-dependent Class III HDACs or sirtuins (Sirts), played an important role in the regulation of CSR and SHM. Sirt1 deacetylated p65, an element of the canonical NF-kB pathway, which mediates AID induction, thereby repressing NF-kB activity. Sirt1 deficiency in B cells led to NF-kB hyperacetylation and activation, which resulted in enhanced AID expression and increased CSR to IgG, IgA and IgE. Conversely, 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, resulted in upregulated AID expression, increased CSR and SHM, and enhanced T-dependent and T-independent antibody response. These 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. Supported by the NIH grants AI 105813, AI 079705 and ALR TIL grant ALR 295955.