Dataset Information

Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

ABSTRACT: The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.

SUBMITTER: Chuang YT

PROVIDER: S-EPMC8621504 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

Chuang Ya-Ting YT Chuang Wan-Chu WC Liu Chih-Chun CC Liu Chia-Wei CW Huang Yu-Wen YW Yang Huang-Yu HY Ho I-Cheng IC Tai Tzong-Shyuan TS

International journal of molecular sciences 20211111 22

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role indep ...[more]

PMID: 34830080

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Project description:Rationale: Cell reprogramming technology is utilized to prevent cancer progression by transforming cells into terminally differentiated, non-proliferating states. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA binding protein required for the growth of neurons and may directly transform multiple normal human cells into functioning neurons in vitro and in vivo when expressed at low levels. As a result, we identified it as a key to inhibiting cancer cell proliferation by boosting glioblastoma cell neural differentiation. Methods: Immunocytofluorescence (ICF) targeting TUJ1, MAP2, KI67, and EdU were utilized to evaluate glioblastoma cell reprogramming under PTBP1 knockdown or other conditions. PTBP1 and other target genes were detected using Western blotting and qRT-PCR. Activating protein phosphatase 2A (PP2A) and RhoA were detected using specific kits. CCK8 assays were employed to detect cell viability. Bioluminescence, immunohistofluorescence (IHF), and Kaplan-Meier survival analyses were utilized to demonstrate the in vivo reprogramming efficiency of PTBP1 knockdown in U87 murine glioblastoma model. In this study, RNA-seq technology was used to examine the intrinsic pathway. Results: The expression of TUJ1 and MAP2 neural markers, as well as the absence of KI67 and EdU proliferative markers in U251, U87, and KNS89 cells, indicated that glioblastoma cell reprogramming was successful. In vivo, U87 growth generated xenografts was substantially shrank due to PTBP1 knockdown induced neural differentiation, and these tumor-bearing mice had a prolonged survival time. Following RNA-seq, ten potential downstream genes were eliminated. Lentiviral interference and inhibitors blocking tests demonstrated that UNC5B receptor and its downstream signaling were essential in the neural differentiation process mediated by PTBP1 knockdown in glioblastoma cells. Conclusions: Our results indicate that PTBP1 knockdown promotes neural differentiation of glioblastoma cells via UNC5B receptor, consequently suppressing cancer cell proliferation in vitro and in vivo, providing a promising and feasible approach for glioblastoma treatment.

Dataset Information

Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

Publications

Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

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