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
Open Access
- 1 April 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 16 (4), e1008515
- https://doi.org/10.1371/journal.ppat.1008515
Abstract
Author summary Type III IFNs (IFN-lambda s) are antiviral cytokines that are thought to act on specific subsets of cells, especially to protect mucosal barriers. Here, we demonstrate that IFN-lambda 3 differentially binds multiple human immune cell subsets, indicating the specific receptor subunit, IFN-lambda R1, is more broadly expressed in the human immune system, compared to published mouse models. IFN-lambda R1 expression increased after cellular activation, and antiviral responses were inhibited by a soluble version of the receptor. The direct interaction of IFN-lambda s with human immune cells, and specific regulation of IFN-lambda R1 expression, has broad mechanistic implications in the modulation of inflammatory or anti-cancer immune responses, and future antiviral therapies. Type III interferons (IFN-lambdas(lambda)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-lambda R1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-lambda s has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-lambda R1 expression and measure the downstream effects of IFN-lambda 3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-lambda 3 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-lambda 3, 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-lambda R1 (sIFN-lambda R1), which significantly reduced ISG induction when added with IFN-lambda 3 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-lambda 3 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.This publication has 83 references indexed in Scilit:
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