Obajemu Adeola A, Rao Nina, Dilley Kari A, Vargas Joselin M, Sheikh Faruk, Donnelly Raymond P, Shabman Reed S, Meissner Eric G, Prokunina-Olsson Ludmila, Onabajo Olusegun O
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Virology Group, J. Craig Venter Institute, Rockville, MD 20850.
J Immunol. 2017 Dec 1;199(11):3808-3820. doi: 10.4049/jimmunol.1700807. Epub 2017 Oct 25.
Type III IFNs are important mediators of antiviral immunity. IFN-λ4 is a unique type III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear hepatitis C virus infection. In this study, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on hepatitis C virus clearance. We used fresh primary human hepatocytes (PHHs) treated with recombinant type III IFNs or infected with Sendai virus to model acute viral infection and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in Sendai virus-infected PHHs from individuals with the dG allele, where it was poorly secreted but highly functional, even at concentrations < 50 pg/ml. IFN-λ4 acted faster than other type III IFNs in inducing antiviral genes, as well as negative regulators of the IFN response, such as and Transient treatment of PHHs with IFN-λ4, but not IFN-λ3, caused a strong and sustained induction of and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.
III型干扰素是抗病毒免疫的重要介质。IFN-λ4是一种独特的III型干扰素，因为它仅在携带基因变体rs368234815-dG/TT的dG等位基因的个体中产生。与直觉相反，那些能够产生抗病毒细胞因子IFN-λ4的个体清除丙型肝炎病毒感染的可能性也较小。在本研究中，我们寻找了IFN-λ4可能解释其对丙型肝炎病毒清除产生负面影响的独特功能特性。我们使用用重组III型干扰素处理或感染仙台病毒的新鲜原代人肝细胞（PHH）来模拟急性病毒感染，随后在HepG2细胞系模型中验证了我们的发现。内源性IFN-λ4蛋白仅在来自具有dG等位基因个体的仙台病毒感染的PHH中可检测到，在那里它分泌不佳但功能高度活跃，即使在浓度<50 pg/ml时也是如此。IFN-λ4在诱导抗病毒基因以及IFN反应的负调节因子（如 和 ）方面比其他III型干扰素作用更快。用IFN-λ4而非IFN-λ3对PHH进行短暂处理会导致 强烈且持续的诱导以及对IFN-λ3进一步刺激的不应性。我们的结果表明IFN-λ4具有独特的功能特性，这在病毒清除和其他临床情况中可能很重要。
