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

Jop Jans,Marien I De Jonge,Ronald De Groot,Wendy W Unger,Elisabeth A M Raeven,Elles R Simonetti,Gerben Ferwerda,Marc J Eleveld

doi:10.3389/fimmu.2021.652965

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.

Highlights

Newborns encounter a large variety of infectious microorganisms during the first months of life
Cord blood mononuclear cells (CBMCs) and adult peripheral blood mononuclear cells (PBMCs) were used to assess whether human newborn T cells are differently modulated by type I IFNs compared to adults
It was demonstrated for the first time that interferon beta (IFN-b) has a low inhibitory effect on human newborn CD4+ T cells with regards to (a) proliferation, (b) phosphorylation of retinoblastoma protein (Rb) and (c) cytokine production upon T cell receptor (TCR) stimulation compared to adult CD4+ T cells

Summary

Introduction

Newborns encounter a large variety of infectious microorganisms during the first months of life. Whereas antibodies are transferred from the mother leading to passive protection, T cell-mediated immunity has to be developed by the newborn itself. A delicate balance between accurate T cell activation and prevention of T cell-mediated immunopathology is essential to mount a protective immune response. The low production of cytokines such as interferon gamma (IFN-g) in newborns indicates a reduced activation of CD4+ T cells [1]. On the other hand, activated CD4+ T cells and T cell-mediated immunopathology has been observed during neonatal sepsis [2] and severe viral infections, including neonatal RSV infections [3]. Type I IFNs, such as interferon alpha (IFN-a) and interferon beta (IFN-b), are key regulators of the adaptive immune response, including CD4+ T cells [4].

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