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

• Published in: PLoS pathogens Vol. 16; no. 4; p. e1008515
• Main Authors: Santer, Deanna M, Minty, Gillian E S, Golec, Dominic P, Lu, Julia, May, Julia, Namdar, Afshin, Shah, Juhi, Elahi, Shokrollah, Proud, David, Joyce, Michael, Tyrrell, D Lorne, Houghton, Michael
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2020; Public Library of Science (PLoS)
• Subjects: Adaptive systems; Alternative splicing; Animal models; Animals; Antibodies; B cells; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biological response modifiers; Biology and Life Sciences; Blood; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Cell Line; Cytokines; Dentistry; Downstream effects; Epithelial cells; Epithelial Cells - metabolism; Flow cytometry; Gene Expression; Genes; Health aspects; Hepatocytes; HIV; HIV Infections - immunology; HIV Infections - pathology; HIV Infections - virology; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune response; Immune system; Immunodeficiency; Immunology; Infections; Interferon; Interferon alpha-2 - pharmacology; Interferon Lambda; Interferons - immunology; Interferons - pharmacology; Killer cells; Leukocytes (mononuclear); Leukocytes (neutrophilic); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Liver; Liver - metabolism; Liver - pathology; Lung - metabolism; Lung - pathology; Lungs; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine and Health Sciences; Mice; Monocytes; Mucosa; Natural killer cells; Neutrophils; Peripheral blood mononuclear cells; Receptors; Receptors, Interferon - biosynthesis; Receptors, Interferon - genetics; Receptors, Interferon - immunology; Research and Analysis Methods; RNA Splicing; Software industry; Stimulation; T cell receptors; T cells; T-cell receptor; Transcription; Virology; Virus diseases; Virus Diseases - genetics; Virus Diseases - immunology; Virus Diseases - metabolism; Viruses; United States; Edmonton Alberta Canada; Canada
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008515

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.