Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development
Abstract Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differenti...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40950-2 |
| _version_ | 1797558273854930944 |
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| author | Keiko Ono Tomohisa Sujino Kentaro Miyamoto Yosuke Harada Satoshi Kojo Yusuke Yoshimatsu Shun Tanemoto Yuzo Koda Jiawen Zheng Kazutoshi Sayama Tsuyoshi Koide Toshiaki Teratani Yohei Mikami Kaoru Takabayashi Nobuhiro Nakamoto Naoki Hosoe Mariya London Haruhiko Ogata Daniel Mucida Ichiro Taniuchi Takanori Kanai |
| author_facet | Keiko Ono Tomohisa Sujino Kentaro Miyamoto Yosuke Harada Satoshi Kojo Yusuke Yoshimatsu Shun Tanemoto Yuzo Koda Jiawen Zheng Kazutoshi Sayama Tsuyoshi Koide Toshiaki Teratani Yohei Mikami Kaoru Takabayashi Nobuhiro Nakamoto Naoki Hosoe Mariya London Haruhiko Ogata Daniel Mucida Ichiro Taniuchi Takanori Kanai |
| author_sort | Keiko Ono |
| collection | DOAJ |
| description | Abstract Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9 −/− mice. CD4+ T cells isolated from the epithelium of Ccr9 −/− mice also display increased expression of Cbfβ2, and the genomic occupancy modification of Cbfβ2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation. |
| first_indexed | 2024-03-10T17:28:58Z |
| format | Article |
| id | doaj.art-f3798e0a3c1041ce9d72da327e0971b3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:28:58Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f3798e0a3c1041ce9d72da327e0971b32023-11-20T10:06:40ZengNature PortfolioNature Communications2041-17232023-08-0114111510.1038/s41467-023-40950-2Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte developmentKeiko Ono0Tomohisa Sujino1Kentaro Miyamoto2Yosuke Harada3Satoshi Kojo4Yusuke Yoshimatsu5Shun Tanemoto6Yuzo Koda7Jiawen Zheng8Kazutoshi Sayama9Tsuyoshi Koide10Toshiaki Teratani11Yohei Mikami12Kaoru Takabayashi13Nobuhiro Nakamoto14Naoki Hosoe15Mariya London16Haruhiko Ogata17Daniel Mucida18Ichiro Taniuchi19Takanori Kanai20Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineCenter for Diagnostic and Therapeutic Endoscopy, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineLaboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical SciencesDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineLaboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical SciencesApplied Life Science Course, College of Agriculture, Shizuoka UniversityMouse Genomics Resource Laboratory, National Institute of GeneticsDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineCenter for Diagnostic and Therapeutic Endoscopy, Keio University School of MedicineDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineCenter for Diagnostic and Therapeutic Endoscopy, Keio University School of MedicineLaboratory of Mucosal Immunology, The Rockefeller UniversityCenter for Diagnostic and Therapeutic Endoscopy, Keio University School of MedicineLaboratory of Mucosal Immunology, The Rockefeller UniversityLaboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical SciencesDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of MedicineAbstract Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9 −/− mice. CD4+ T cells isolated from the epithelium of Ccr9 −/− mice also display increased expression of Cbfβ2, and the genomic occupancy modification of Cbfβ2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation.https://doi.org/10.1038/s41467-023-40950-2 |
| spellingShingle | Keiko Ono Tomohisa Sujino Kentaro Miyamoto Yosuke Harada Satoshi Kojo Yusuke Yoshimatsu Shun Tanemoto Yuzo Koda Jiawen Zheng Kazutoshi Sayama Tsuyoshi Koide Toshiaki Teratani Yohei Mikami Kaoru Takabayashi Nobuhiro Nakamoto Naoki Hosoe Mariya London Haruhiko Ogata Daniel Mucida Ichiro Taniuchi Takanori Kanai Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development Nature Communications |
| title | Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development |
| title_full | Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development |
| title_fullStr | Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development |
| title_full_unstemmed | Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development |
| title_short | Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development |
| title_sort | downregulation of chemokine receptor 9 facilitates cd4 cd8αα intraepithelial lymphocyte development |
| url | https://doi.org/10.1038/s41467-023-40950-2 |
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