Negative regulation of activation-induced cytidine deaminase in B cells

Abstract

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). AID expression in non-B cells such as fibroblasts and T cells can induce CSR and SHM on transfected artificial constructs if the target DNA is actively transcribed (11-13). Therefore, AID and target transcription appear to be essential and sufficient for CSR and SHM in non-B as well as B cells. However, studies on transgenic (Tg) mouse lines ubiquitously expressing AID showed neither distortion of the B220 ϩ B cell population nor increase in serum IgG levels (14). Although all mice died by 80 weeks because of T cell lymphomas, no B cell lymphomas were observed in the Tg mice (14). These observations have raised a possibility that Tg AID is negatively regulated in B cells. However, we could not exclude the possibility that dysregulation of T cells by a very early onset of T lymphomas may perturb B cell responses in AID-Tg mice.It is therefore important to test the effects of constitutive AID expression in B cells using a more defined system. We thus generated Tg mice, which express AID constitutively only in B cells, and crossed them with AID-deficient mice. Using this system, we found that the Tg AID, despite its abundance, is much less efficient for CSR and SHM than the endogenous AID, suggesting that AID is negatively regulated in B cells.

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

“…The fact that the γ1PST defect is worse (5-fold down) than the AID defect (about 3-fold down) (see Fig. 2A) in aging in response to anti-CD40/IL-4 is consistent with Honjo's recent paper (Muto et al, 2006) showing that AID alone is not sufficient to improve class switch in B cells (therefore effects of E47 may also be on accessibility/transcription of the rearranged Ig locus/other factors influencing CSR in addition to increasing AID).…”

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…We reported earlier the lack of lymphomagenesis in B-cellspecific AID transgenic mice obtained by crossing the same AID cTg line with CD19-Cre mice (Muto et al, 2006), suggesting that some protective mechanism might exist in B cells, which have physiological expression of AID. A similar reason might apply to germ cells because AID has been reported to be expressed physiologically in the human testis (Schreck et al, 2006) and mouse ovary (Morgan et al, 2004).…”

“…AID cTg mice possess a CAG promoter-driven AID transgene, whose expression is blocked by insertion of the gene encoding enhanced green fluorescent protein (hereafter GFP) flanked by two loxP sites (Figure 1a). Therefore, the expression of Cre recombinase removes GFP and induces AID expression (Muto et al, 2006). TNAPCre mice were generated by inserting the coding sequence of Cre recombinase into the Akp2 locus of the 129/Sv mouse genome, and Cre was expressed in primordial germ cells in the embryonic genital ridge region (Lomeli et al, 2000).…”

“…The AID cTg mice (line 20) on a C57BL/6 background (Muto et al, 2006) were self-crossed to obtain homozygous transgenic mice, which were maintained in a specific pathogen-free facility at the Kyoto University Faculty of Medicine and Shiga Medical Center. This mouse line has been deposited at the Riken Bioresource Center (Tsukuba, Japan; No.…”

“…We generated earlier AID transgenic mice that can express AID conditionally in a Cre-recombianasedependent manner (AID conditional transgenic, AID cTg) and reported B-cell-specific AID transgenic mice obtained by crossing AID cTg mice with B-cell-specific Cre transgenic mice (Muto et al, 2006). In this study, we used a different Cre transgenic mouse line that expresses Cre in cells producing tissue nonspecific alkaline phosphatase (TNAP), as the mating partner of AID cTg mice.…”