Dataset Information

Lack of Cell Cycle Inhibitor p21 and Low CD4⁺ T Cell Suppression in Newborns After Exposure to IFN-β.

ABSTRACT: Type I IFNs, such as interferon alpha and interferon beta, are key regulators of the adaptive immune response during infectious diseases. Type I IFNs are induced upon infection, bind interferon α/β receptors on T-cells and activate intracellular pathways. The activating and inhibitory consequences of type I IFN-signaling are determined by cell type and cellular environment. The neonatal immune system is associated with increased vulnerability to infectious diseases which could partly be explained by an immature CD4⁺ T-cell compartment. Here, we show low IFN-β-mediated inhibition of CD4⁺ T-cell proliferation, phosphorylation of retinoblastoma protein and cytokine production in human newborns compared to adults. In addition, both naïve and total newborn CD4⁺ T-cells are unable to induce the cell-cycle inhibitor p21 upon exposure to IFN-β in contrast to adults. The distinct IFN-β-signaling in newborns provides novel insights into T cell functionality and regulation of T cell-dependent inflammation during early life immune responses.

SUBMITTER: Jans J

PROVIDER: S-EPMC8071872 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Lack of Cell Cycle Inhibitor p21 and Low CD4<sup>+</sup> T Cell Suppression in Newborns After Exposure to IFN-β.

Jans Jop J Unger Wendy W WW Raeven Elisabeth A M EAM Simonetti Elles R ER Eleveld Marc J MJ de Groot Ronald R de Jonge Marien I MI Ferwerda Gerben G

Frontiers in immunology 20210412

Type I IFNs, such as interferon alpha and interferon beta, are key regulators of the adaptive immune response during infectious diseases. Type I IFNs are induced upon infection, bind interferon α/β receptors on T-cells and activate intracellular pathways. The activating and inhibitory consequences of type I IFN-signaling are determined by cell type and cellular environment. The neonatal immune system is associated with increased vulnerability to infectious diseases which could partly be explaine ...[more]

PMID: 33912177

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Project description:The Ets family of transcription factors control a myriad of cellular processes and contribute to the underlying genetic loss of cellular homeostasis resulting in cancer. PDEF (prostate-derived Ets factor) has been under investigation for its role in tumor development and progression. However, the role of PDEF in cancer development has been controversial. Some reports link PDEF to tumor promoter, and others show tumor-suppressing functions in various systems under different conditions. So far, there has been no conclusive evidence from in vivo experiments to prove the role of PDEF. We have used both in vitro and in vivo systems to provide a conclusive role of PDEF in the progression process. PDEF-expressing cells block the cell growth rate, and this retardation was reversible when PDEF expression was silenced with PDEF-specific small interfering RNA. When these PDEF-expressing cells were orthotopically implanted into the mouse mammary gland, tumor incidence and growth rate were significantly retarded. Cell cycle analysis revealed that PDEF expression partially blocked cell cycle progression at G(1)/S without an effect on apoptosis. PDEF overexpression resulted in an increase in p21/CIP1 at both the mRNA and protein levels, resulting in decreased Cdk2 activity. Promoter deletion analysis, electrophoresis mobility shift assays, and chromatin immunoprecipitation studies identified the functional Ets DNA binding site at -2118 bp of the p21/CIP1 gene promoter. This site is capable of binding and responding to PDEF. Furthermore, we silenced p21/CIP1 expression in PDEF-overexpressing cells by small interfering RNA. p21-silenced PDEF cells exhibited significantly increased cell growth in vitro and in vivo, demonstrating the p21 regulation by PDEF as a key player. These experiments identified PDEF as a new transcription factor that directly regulates p21/CIP1 expression under non-stressed conditions. This study conclusively proves that PDEF is a breast tumor suppressor for the first time using both in vitro and in vivo systems. PDEF can be further developed as a target for designing therapeutic intervention of breast cancer.

Dataset Information

Lack of Cell Cycle Inhibitor p21 and Low CD4⁺ T Cell Suppression in Newborns After Exposure to IFN-β.

Publications

Lack of Cell Cycle Inhibitor p21 and Low CD4<sup>+</sup> T Cell Suppression in Newborns After Exposure to IFN-β.

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Dataset Information

Lack of Cell Cycle Inhibitor p21 and Low CD4+ T Cell Suppression in Newborns After Exposure to IFN-β.

Publications

Lack of Cell Cycle Inhibitor p21 and Low CD4<sup>+</sup> T Cell Suppression in Newborns After Exposure to IFN-β.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Lack of Cell Cycle Inhibitor p21 and Low CD4⁺ T Cell Suppression in Newborns After Exposure to IFN-β.