Laboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
Laboratory of Molecular Biology, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
Immunity. 2017 May 16;46(5):875-890.e6. doi: 10.1016/j.immuni.2017.04.025.
Lambda interferons (IFNλs) or type III IFNs share homology, expression patterns, signaling cascades, and antiviral functions with type I IFNs. This has complicated the unwinding of their unique non-redundant roles. Through the systematic study of influenza virus infection in mice, we herein show that IFNλs are the first IFNs produced that act at the epithelial barrier to suppress initial viral spread without activating inflammation. If infection progresses, type I IFNs come into play to enhance viral resistance and induce pro-inflammatory responses essential for confronting infection but causing immunopathology. Central to this are neutrophils which respond to both cytokines to upregulate antimicrobial functions but exhibit pro-inflammatory activation only to type I IFNs. Accordingly, Ifnlr1 mice display enhanced type I IFN production, neutrophilia, lung injury, and lethality, while therapeutic administration of PEG-IFNλ potently suppresses these effects. IFNλs therefore constitute the front line of antiviral defense in the lung without compromising host fitness.
λ 干扰素（IFNλs）或 III 型干扰素与 I 型干扰素具有同源性、表达模式、信号级联和抗病毒功能。这使得它们独特的非冗余作用变得复杂。通过对小鼠流感病毒感染的系统研究，我们在此表明 IFNλs 是最早产生的干扰素，在病毒初始传播时作用于上皮屏障以抑制病毒扩散，而不会引发炎症。如果感染继续发展，I 型干扰素发挥作用以增强病毒抵抗力并诱导对感染至关重要的促炎反应，但会导致免疫病理。这其中的关键是中性粒细胞，它对两种细胞因子作出反应，上调抗菌功能，但仅对 I 型干扰素表现出促炎激活。因此，Ifnlr1 小鼠表现出增强的 I 型 IFN 产生、中性粒细胞增多、肺损伤和致死性，而 PEG-IFNλ 的治疗性给药则有力地抑制了这些效应。IFNλs 因此构成了肺部抗病毒防御的第一道防线，而不会损害宿主适应性。
