Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCRαβ+CD8αα+ T cells
Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCRαβ+CD8αα+ T cells
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DOI：
10.1371/journal.pbio.3000262
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发表时间：
2019-05
期刊：
影响因子：
9.8
通讯作者：
Chieko Ishifune;S. Tsukumo;Y. Maekawa;K. Hozumi;D. Chung;Chihiro Motozono;S. Yamasaki;H. Nakano;K. Yasutomo
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文献类型：
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作者：
Chieko Ishifune;S. Tsukumo;Y. Maekawa;K. Hozumi;D. Chung;Chihiro Motozono;S. Yamasaki;H. Nakano;K. Yasutomo
在αβ T细胞上表达CD 8 αα的肠上皮内淋巴细胞（IEL）（TCRαβ+ CD 8 αα+ IEL）在小肠结肠炎中具有抑制能力，但维持稳态和细胞数量的机制尚未完全了解。在这里，我们证明了在T细胞中缺乏免疫球蛋白κ J区（Rbpj）或Notch 1和Notch 2的重组信号结合蛋白的小鼠中，TCRαβ+ CD 8 αα+ IEL的数量严重减少。Rbpj缺陷型TCRαβ+ CD 8 αα+ IEL表达低水平的Atp 8a 2，其编码具有翻转酶活性的蛋白，调节质膜的磷脂不对称性，例如翻转质膜内小叶中的磷脂酰丝氨酸。Rbpj缺陷型TCRαβ+ CD 8 αα+ IEL不能维持质膜内叶中的磷脂酰丝氨酸。此外，在Rbpj缺陷型小鼠中，肠道巨噬细胞的消耗恢复了TCRαβ+ CD 8 αα+ IEL，这表明在Rbpj缺陷型TCRαβ+ CD 8 αα+ IEL中，质膜上的磷脂酰丝氨酸的暴露起到了“吃我”信号的作用。总之，这些结果揭示了Notch-Atp 8a 2是IEL的基本调节剂，并强调了由Notch介导的翻转酶表达控制的膜磷脂不对称性是设定或平衡TCRαβ+ CD 8 αα+ IEL数量的关键决定因素。
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.