Nature Communications (Aug 2023)

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,
  • Takanori Kanai

DOI
https://doi.org/10.1038/s41467-023-40950-2
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 15

Abstract

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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.