Activation-Induced Cytidine Deaminase Expression in CD4+ T Cells is Associated with a Unique IL-10-Producing Subset that Increases with Age

Abstract

Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4+ T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4+ and B220+ cell populations. ExAID B cells remained IgM+, suggesting that class-switched memory B cells do not accumulate in the spleen. In T cells, AID was expressed in a subset that produced IFN-γ and IL-10 but little IL-4 or IL-17, and showed no evidence of genetic mutation. Interestingly, the endogenous Aicda expression in T cells was enhanced in the absence of B cells, indicating that the process is independent from the germinal center reaction. These results suggest that in addition to its roles in B cells, AID may have previously unappreciated roles in T-cell function or tumorigenesis.

Activation-induced cytidine deaminase and active cytidine demethylation

“…This is best illustrated by the conflicting results in iPSCs [33][34][35][36] and heterokaryons [27,29], and by the difficulty in reconciling reports of AID-driven demethylation in the germline [30,31] with the evidence that these cells express little AID [44,63,[65][66][67]. The elucidation of these issues will come from the empirical investigation of the questions listed in Box 1.…”

“…Data from genome-wide demethylation studies [30,34,41,42] duced in mice [63]. Notably, three independently generated Aicda-CrexROSA26-EYFP gene-tracing mouse strains did not find evidence for the transcription of the Aicda locus in the germline and pluripotent tissues ( [65][66][67]; Cortesã o and V.M.B., unpublished), which shows that AID expression, if any, is below the threshold of detection of these tracer lines. Thus, there is currently little evidence that AID is expressed in the germline.…”

Both CpG Methylation and Activation-Induced Deaminase Are Required for the Fragility of the Human bcl-2 Major Breakpoint Region: Implications for the Timing of the Breaks in the t(14;18) Translocation

“…Because these B cell translocations occur during V(D)J recombination (the IgH breaks at chromosome 14 require RAGs), our model proposed concurrent expression of both AID and the RAG complex as requirements. Recent studies have documented AID mRNA and AID enzymatic activity in mouse and human pro-B and pre-B cells (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Therefore, AID may potentially play a role in translocations in these B cells.…”

Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

“…Similar to CVID, several subtypes of hyper-IgM syndrome (including defects in CD40LG, AID or IKBKG) can present with IBD-like immunopathology but again the colitogenic defect might be non-B cell intrinsic as the CD40 ligand encoded by the CD40LG gene is largely expressed by activated T lymphocytes; the activation induced cytidine deaminase (AID) gene is not only expressed on B cells but might play a role for IL-10 secreting T cells66 and NEMO deficiency induced IBD-like pathology is most likely due to an epithelial defect (as discussed above).…”