| The B cell response is a crucial part of adaptive immunity, secreting antibodies that recognize a seemingly unlimited number of pathogens. They accomplish this monumental task by participating in two reactions, known as somatic hypermutation and class switch recombination, that serve to increase antibody affinity and direct their functional characteristics, respectively. Both of these mutational reactions are induced through the activity of activation-induced cytidine deaminase (AID), whose purpose is to deaminate cytidines residues within the immunoglobulin locus. AID, however, is prone to infidelity and highly mutagenic. Not surprisingly, it has been implicated in the development of numerous cancers, both solid and liquid. As such, understanding how AID is regulated is of the utmost importance.;In recent years, a new role for AID in active demethylation has come to light. While the exact mechanism of action remains elusive, several studies have implicated AID in the demethylation that occurs during both developmental processes and artificially induced cellular reprogramming. We have recently shown that AID is required during the fibroblast reprogramming process to demethylate the genes needed for stabilization of the pluripotent state. This led us to pursue transcription factor-mediated reprogramming in activated B cells, where AID levels are naturally highest, with the intent of identifying targeting factors or interactors. While our reprogramming attempts were unsuccessful, they led to the discovery of two novel regulators of class switching: Sox2 and Klf4. We show, for the first time, that Sox2 is expressed in stimulated B cells and that both Sox2 and Klf4 expression are sufficient to terminate switching by regulating AID levels and germline transcription. By employing RNA-Seq analysis, we have found that Sox2 may be exerting its effects on switching through repression of the known AID regulators Batf and Irf4. Klf4, on the other hand, is involved in a negative feedback loop with Foxo1, another transcription factor required for AID expression and switching. These findings not only provide insight into yet another regulatory pathway confining expression of this dangerous enzyme, but may also have implications for preventing excessive AID expression in the reprogramming setting. |
