Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells

Autor: Juhi Shah, D. Lorne Tyrrell, Julia May, Michael A. Joyce, Gillian E. S. Minty, Julia Lu, Afshin Namdar, Dominic P. Golec, Shokrollah Elahi, Michael Houghton, Deanna M. Santer, David Proud
Jazyk: angličtina
Rok vydání: 2020
Předmět:
CD4-Positive T-Lymphocytes
B Cells
Neutrophils
Gene Expression
HIV Infections
Epithelium
Monocytes
Interferon Lambda
White Blood Cells
Binding Analysis
Mice
Interferon
Animal Cells
Gene expression
Medicine and Health Sciences
Biology (General)
Receptor
Lung
Receptors
Interferon
0303 health sciences
B-Lymphocytes
Chemistry
T Cells
030302 biochemistry & molecular biology
Acquired immune system
Liver
Virus Diseases
Cellular Types
Anatomy
Cell Binding Assay
medicine.drug
Research Article
Cell Binding
Cell Physiology
QH301-705.5
Immune Cells
RNA Splicing
Immunology
Interferon alpha-2
Research and Analysis Methods
Microbiology
Peripheral blood mononuclear cell
Cell Line
03 medical and health sciences
Immune system
Virology
Genetics
medicine
Animals
Humans
Antibody-Producing Cells
Molecular Biology
Chemical Characterization
030304 developmental biology
Blood Cells
Biology and Life Sciences
Epithelial Cells
Cell Biology
RC581-607
Molecular biology
Biological Tissue
Cell culture
HIV-1
Leukocytes
Mononuclear
Parasitology
Interferons
Immunologic diseases. Allergy
CD8
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 16, Iss 4, p e1008515 (2020)
ISSN: 1553-7374
1553-7366
Popis: Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.
Author summary Type III IFNs (IFN-λs) are antiviral cytokines that are thought to act on specific subsets of cells, especially to protect mucosal barriers. Here, we demonstrate that IFN-λ3 differentially binds multiple human immune cell subsets, indicating the specific receptor subunit, IFN-λR1, is more broadly expressed in the human immune system, compared to published mouse models. IFN-λR1 expression increased after cellular activation, and antiviral responses were inhibited by a soluble version of the receptor. The direct interaction of IFN-λs with human immune cells, and specific regulation of IFN-λR1 expression, has broad mechanistic implications in the modulation of inflammatory or anti-cancer immune responses, and future antiviral therapies.
Databáze: OpenAIRE
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