Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development

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 and Takanori Kanai ()
Additional contact information
Keiko Ono: Keio University School of Medicine
Tomohisa Sujino: Keio University School of Medicine
Kentaro Miyamoto: Keio University School of Medicine
Yosuke Harada: Keio University School of Medicine
Satoshi Kojo: RIKEN Center for Integrative Medical Sciences
Yusuke Yoshimatsu: Keio University School of Medicine
Shun Tanemoto: Keio University School of Medicine
Yuzo Koda: Keio University School of Medicine
Jiawen Zheng: RIKEN Center for Integrative Medical Sciences
Kazutoshi Sayama: Shizuoka University
Tsuyoshi Koide: National Institute of Genetics
Toshiaki Teratani: Keio University School of Medicine
Yohei Mikami: Keio University School of Medicine
Kaoru Takabayashi: Keio University School of Medicine
Nobuhiro Nakamoto: Keio University School of Medicine
Naoki Hosoe: Keio University School of Medicine
Mariya London: The Rockefeller University
Haruhiko Ogata: Keio University School of Medicine
Daniel Mucida: The Rockefeller University
Ichiro Taniuchi: RIKEN Center for Integrative Medical Sciences
Takanori Kanai: Keio University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40950-2

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