Regulation of AID Function In Vivo

Abstract

Extensive proliferation of antigen–stimulated B lymphocytes is accompanied by two distinct genetic alterations, namely somatic hypermutation (SHM) and class switch recombination (CSR).1 SHM introduces point mutations at high frequency in DNA encoding variable (V) regions of immunoglobulin (Ig) and their immediate downstream flanking region, followed by selection in germinal centers for high-affinity antibody-producing cells against a given antigen. On the other hand, CSR takes place between repetitive DNA sequences (S regions) located 5’ to Ig heavy chain constant-region genes. CSR is a region-specific recombination to diversify effector functions of Ig by changing Ig isotypes from IgM to IgG, IgE, or IgA. Activation-induced cytidine deaminase (AID) is required for both CSR and SHM because AID deficiency in mouse and human completely abolishes these two genetic alterations. 2,3 In addition to AID, CSR and SHM require transcription of target DNAs, S regions and V regions, respectively. 4−10 All of the other factors required for CSR and SHM appear to be expressed ubiquitously because the two reactions can be induced by AID overexpression in non-B cells such as fibroblasts if the target DNA is actively transcribed.11−13 However, studies on transgenic (Tg) mouse lines ubiquitously expressing AID suffered from T cell lymphomas or lung microadenomas but not B cell lymphomas,14 indicating a possibility that transgenic AID is negatively regulated in B cells. In addition, we have recently shown that the transgenic AID expressed constitutively only in B cells, albeit its abundance, is much less efficient for CSR and SHM than the endogenous AID, suggesting that AID is negatively regulated in B cells or unknown modification is necessary for full activation of AID.15 Recently Basu et al. reported that phosphorylation of AID by protein kinase A (PKA) is critical to class switch recombination (CSR) in B cells. 16 They found