AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D 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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505348 |
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| author | Arantxa Pérez‐García Pablo Pérez‐Durán Thomas Wossning Isora V Sernandez Sonia M Mur Marta Cañamero Francisco X Real Almudena R Ramiro |
| author_facet | Arantxa Pérez‐García Pablo Pérez‐Durán Thomas Wossning Isora V Sernandez Sonia M Mur Marta Cañamero Francisco X Real Almudena R Ramiro |
| author_sort | Arantxa Pérez‐García |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f845f41e876b414eaa2cf320fdb7f77d |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-f845f41e876b414eaa2cf320fdb7f77d2025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-08-017101327133610.15252/emmm.201505348AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathwayArantxa Pérez‐García0Pablo Pérez‐Durán1Thomas Wossning2Isora V Sernandez3Sonia M Mur4Marta Cañamero5Francisco X Real6Almudena R Ramiro7B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Roche Diagnostics GmbHEpithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO)B Cell Biology Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)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.https://doi.org/10.15252/emmm.201505348activation‐induced deaminasecancerepitheliumNKG2Dpancreas |
| spellingShingle | Arantxa Pérez‐García Pablo Pérez‐Durán Thomas Wossning Isora V Sernandez Sonia M Mur Marta Cañamero Francisco X Real Almudena R Ramiro AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway EMBO Molecular Medicine activation‐induced deaminase cancer epithelium NKG2D pancreas |
| title | AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway |
| title_full | AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway |
| title_fullStr | AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway |
| title_full_unstemmed | AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway |
| title_short | AID‐expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway |
| title_sort | aid expressing epithelium is protected from oncogenic transformation by an nkg2d surveillance pathway |
| topic | activation‐induced deaminase cancer epithelium NKG2D pancreas |
| url | https://doi.org/10.15252/emmm.201505348 |
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