Regulation of membrane phospholipid asymmetry by Notch-mediated flippase expression controls the number of intraepithelial TCR??+CD8??+ T cells.

ABSTRACT: Intestinal intraepithelial lymphocytes (IELs) expressing CD8?? on ?? T cells (TCR??+CD8??+ 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 TCR??+CD8??+ 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 TCR??+CD8??+ 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 TCR??+CD8??+ IELs cannot maintain phosphatidylserine in the inner leaflet of the plasma membrane. Furthermore, depletion of intestinal macrophages restored TCR??+CD8??+ IELs in Rbpj-deficient mice, suggesting that exposure of phosphatidylserine on the plasma membrane in Rbpj-deficient TCR??+CD8??+ 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 TCR??+CD8??+ IELs.

SUBMITTER: Ishifune C 

PROVIDER: S-EPMC6529014 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature