AID ‐expressing epithelium is protected from oncogenic transformation by an NKG 2D surveillance pathway

Abstract

Activation-induced deaminase (AID) initiates secondary antibody diversification in germinal center B cells, giving rise to higher affinity antibodies through somatic hypermutation (SHM) or to isotype-switched antibodies through class switch recombination (CSR). SHM and CSR are triggered by AID-mediated deamination of cytosines in immunoglobulin genes. Importantly, AID activity in B cells is not restricted to Ig loci and can promote mutations and pro-lymphomagenic translocations, establishing a direct oncogenic mechanism for germinal center-derived neoplasias. AID is also expressed in response to inflammatory cues in epithelial cells, raising the possibility that AID mutagenic activity might drive carcinoma development. We directly tested this hypothesis by generating conditional knock-in mouse models for AID overexpression in colon and pancreas epithelium. AID overexpression alone was not sufficient to promote epithelial cell neoplasia in these tissues, in spite of displaying mutagenic and genotoxic activity. Instead, we found that heterologous AID expression in pancreas promotes the expression of NKG2D ligands, the recruitment of CD8+ T cells, and the induction of epithelial cell death. Our results indicate that AID oncogenic potential in epithelial cells can be neutralized by immunosurveillance protective mechanisms.

Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID

“…In order to achieve this, we made use of a conditional mouse model for Aid expression where a cassette harboring the Aicda and EGFP cDNAs separated by an internal ribosomal entry site (IRES) sequence was placed inside the Rosa26 endogenous locus. The Aid-EGFP cassette is preceded by a floxed transcriptional stop sequence that prevents Aicda expression ( Rosa26 +/Aid mice 31 ; Supplementary Fig. 12).…”

“…Rosa26 AID knock-in mice were generated by our group and described previously 31 . Rosa26 AID mice were crossed with Mb-1 cre 32 , , P53 −/− 37 , and Ink4/Arf −/− 50 , , respectively.…”

Faecal microbiota transplantation protects against radiation‐induced toxicity

“…Briefly, small intestine tissues were fixed in 4% paraformaldehyde solution overnight, and 4‐μm paraffin sections were processed to performed H&E and IHC staining. For H&E staining, the sections were dipped in haematoxylin for 10 min and eosin for 3 min (Perez‐Garcia et al , ). For IHC staining, primary antibody of anti‐F8 (M0616, Dako, Glostrup, Denmark) was used (Koo et al , ).…”

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“…To address the contribution of AID activity to B cell lymphomagenesis we made use of a conditional mouse model for AID expression [52]. A cassette containing the Aicda and EGFP cDNAs separated by an internal ribosomal entry site (IRES) was placed into the endogenous Rosa26 locus preceded by a floxed transcriptional stop sequence (R26 +/AID mice, S1A Fig, [52]). Thus, AID expression from the Rosa26-Aicda allele is silent until the transcriptional stop is removed by Cre.…”

“…R26 +/AID mice were described previously [52] and bred to Cd19 cre [53], Vav-Cre TG/+ [56] Tp53 -/- [75] and Ung -/- [76] mice as indicated. Aicda -/- [10] were used as negative control for SHM assays.…”