Interferon-λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract

Abstract

Type III interferons (IFNs), also termed lambda IFNs (IFNλs) or interleukins-28/29, constitute a new addition to the IFN family. They are induced upon infection and are particularly abundant at barrier surfaces, such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLR1 and IL10RB, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets, and biological activities and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Type III IFNs are, therefore, arising as front-line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases, including influenza virus infection and asthma.

Keywords: asthma; cytokines; infection; innate immunity; interferons; respiratory tract diseases.

Figure 1

Fine tuning of the innate antiviral immune response by type I and type III interferons (IFNs) in the lung. Type III IFNs are produced first, upon infection of airway epithelial cells, and act as the first line of defense to limit virus spread at the epithelial barrier without triggering inflammation. If infection escapes type III IFN control, type I IFNs are induced that provide the second line of defense, enhancing viral resistance beyond the respiratory epithelium and activating pro-inflammatory responses essential for providing protection but also causing immunopathology.

Figure 2

Immune modulatory and antiviral functions of type III interferons (IFNs) in asthma. Steady-state production of type III IFNs during stable asthma suppresses effector Th2 cell responses and keeps chronic inflammation and disease symptoms under control. Deficient or lower type III IFN production leads to reduced control of Th2 cell responses and chronic inflammation, and renders patients more susceptible to viral infections, both leading to more frequent and more severe asthma exacerbations. A similar mechanism of deficient type III IFN production may also account for chronic obstructive pulmonary disease exacerbations.