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PLoS Biol. 2019 May 9;17(5):e3000262. doi: 10.1371/journal.pbio.3000262. eCollection 2019 May.

Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCRαβ+CD8αα+ T cells.

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Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
Department of Interdisciplinary Researches for Medicine and Photonics, Institute of Post-LED Photonics, Tokushima University, Tokushima, Japan.
Department of Parasitology and Infectious Diseases, Gifu University Graduate School of Medicine, Gifu, Japan.
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan.
Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Department of Biochemistry, School of Medicine, Toho University, Tokyo, Japan.
The Research Cluster program on Immunological diseases, Tokushima University, Tokushima, Japan.


Intestinal intraepithelial lymphocytes (IELs) expressing CD8αα on αβ T cells (TCRαβ+CD8αα+ IELs) have suppressive capabilities in enterocolitis, but the mechanism that maintains homeostasis and cell number is not fully understood. Here, we demonstrated that the number of TCRαβ+CD8αα+ IELs was severely reduced in mice lacking recombination signal binding protein for immunoglobulin kappa J region (Rbpj) or Notch1 and Notch2 in T cells. Rbpj-deficient TCRαβ+CD8αα+ IELs expressed low levels of Atp8a2, which encodes a protein with flippase activity that regulates phospholipid asymmetry of plasma membrane such as flipping phosphatidylserine in the inner leaflet of plasma membrane. Rbpj-deficient TCRαβ+CD8αα+ IELs cannot maintain phosphatidylserine in the inner leaflet of the plasma membrane. Furthermore, depletion of intestinal macrophages restored TCRαβ+CD8αα+ IELs in Rbpj-deficient mice, suggesting that exposure of phosphatidylserine on the plasma membrane in Rbpj-deficient TCRαβ+CD8αα+ IELs acts as an "eat-me" signal. Together, these results revealed that Notch-Atp8a2 is a fundamental regulator for IELs and highlighted that membrane phospholipid asymmetry controlled by Notch-mediated flippase expression is a critical determinant in setting or balancing the number of TCRαβ+CD8αα+ IELs.

Conflict of interest statement

The authors have declared that no competing interests exist.

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