Abstract
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.
Highlights
The intestines face various foreign antigens on their mucosal interface and possess an integrated immunological system that can prevent the dissemination of both commensal and pathogenic microorganisms [1][2][3]
In order to assess how Notch signaling affects the number of intestinal intraepithelial lymphocyte (IEL), we analyzed IELs in the small intestine of Rbpjflox/flox mice crossed with CD4-Cre transgenic mice (Rbpj−/−) and control Rbpj+/+ mice crossed with CD4-Cre transgenic (Rbpj+/+) mice aged 8–10 wk
The data are shown as mean ± S.D., and indicates p < 0.001 (n = 9).The data are representative of three independent experiments. (D) The number of TCRαβ+CD8αα+ cells in Rbpj−/− and Rbpj+/+ mice in lamina propria was evaluated by flow cytometry
Summary
The intestines face various foreign antigens on their mucosal interface and possess an integrated immunological system that can prevent the dissemination of both commensal and pathogenic microorganisms [1][2][3]. The developmental pathway of TCRαβ+CD8αα+ IEL is still poorly understood. TCRαβ+CD8αα+ IEL precursors develop by recognizing high-affinity self-antigen agonists [7] [8]. Two thymic precursors of TCRαβ+CD8αα+ IEL were reported among TCRβ+CD4−CD8− thymocytes, defined by dependence on transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) and other markers [9]. The further differentiation of TCRαβ+CD8αα+ IELs is regulated by interleukin 15 (IL-15) or TGF-β [10] [11]. TGF-β signaling regulates the CD8α expression in thymic precursors of TCRαβ+CD8αα+ IELs [11]. The production of IL-15 from intestinal epithelial cells is required for maintaining TCRαβ+CD8αα+ IELs [12]. The molecular pathways that control the development or number of TCRαβ+CD8αα+ IELs remain largely undetermined
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