Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NF B

Abstract

Activation‐induced cytidine deaminase (AID) is an inducible gene that plays an important role in class switch recombination, somatic hypermutation and gene conversion in B cells. We examined the regulation of AID gene expression in human and mouse B cells by IL‐4 and CD40 ligation. IL‐4 by itself and, to a much lesser extent, CD40 ligation induced AID mRNA expression in primary B cells. The two stimuli strongly synergized in inducing AID mRNA and protein expression. IL‐4 induced STAT6 binding to a site in the 5′ upstream region of the AID gene, while CD40 ligation induced NFκB binding to two sites in that region. B cells from STAT6^–/– mice failed to up‐regulate AID in response to IL‐4, while B cells from p50^–/– mice were impaired in their ability to up‐regulate AID in response to CD40 ligation and IL‐4. These results suggest that signals delivered via CD40 that activate NFκB synergize with signals delivered via the IL‐4 receptor that activate STAT6 to induce optimal AID gene expression.