Interferon Lambda Genetics and Biology in Regulation of Viral Control

Abstract

Type III interferons, also known as interferon lambdas (IFNλs), are the most recent addition to the IFN family following their discovery in 2003. Initially, IFNλ was demonstrated to induce expression of interferon-stimulated genes and exert antiviral properties in a similar manner to type I IFNs. However, while IFNλ has been described to have largely overlapping expression and function with type I IFNs, it has become increasingly clear that type III IFNs also have distinct functions from type I IFNs. In contrast to type I IFNs, whose receptor is ubiquitously expressed, type III IFNs signal and function largely at barrier epithelial surfaces, such as the respiratory and gastrointestinal tracts, as well as the blood-brain barrier. In further support of unique functions for type III IFNs, single nucleotide polymorphisms in IFNL genes in humans are strongly associated with outcomes to viral infection. These biological linkages have also been more directly supported by studies in mice highlighting roles of IFNλ in promoting antiviral immune responses. In this review, we discuss the current understanding of type III IFNs, and how their functions are similar to, and different from, type I IFN in various immune cell subtypes and viral infections.

Keywords: immune cells; immunity; infectious disease; interferon; interferon lambda; virus.

Figure 1

General induction and receptor signaling pathways of type I and type III IFNs. Recognition of virus by multiple pattern recognition receptor pathways leads to the activation of the transcription factors IRF1, IRF3, IRF7, and NF-κB to induce transcription, translation, and secretion of type I IFN (IFNα and IFNβ) and type III IFN [interferon lambda (IFNλ)]. Type I and type III IFNs signal to surrounding cells via distinct receptors to induce activation of the JAK–STAT pathway leading to the production of IFN-stimulated genes (ISGs) that can amplify the IFN signal and induce an antiviral state in infected cells/tissues.

Figure 2

Interferon lambda (IFNλ) and IFNα/β differentially modulate immune responses during acute viral infection and tissue inflammation. (A) Following viral infection/tissue inflammation, IFNλ modulates functions of dendritic cells (DCs) neutrophils, CD4 T cells, and the B-cell antibody response. IFNλ signaling may also regulate macrophage, NK cell, and CD8 T cell function during infection/tissue inflammation (B) type I IFN (IFNα and IFNβ) have been the subject of a greater number of studies and have more defined roles during virus infection and tissue inflammation. Type I IFN enhances functions of DCs, macrophages, NK cells, B cells, CD4 T cells, and CD8 T cells toward an inflammatory/antiviral state.