Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

Abstract

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.

Keywords: IFNα subtypes; IFNβ; autoimmunity; cancer; infection; type I interferons.

Figure 1

Type I IFNs are a closely related family of related cytokines. (A) Depicted is a summary of existing phylogenetic analyses of the type I IFNs. The branches are not drawn to scale. IFNκ, IFNβ, and IFNϵ are mostly present in placental mammals as single copies and the first subtypes to diverge from the other type I IFNs. IFNβ and IFNϵ are especially similar and can be found within the same clade in some analyses. IFNδ and IFNζ are the next subtypes to diverge and are only found in pigs and mice, respectively. IFNτ and IFNω are closely related, despite their differences in function and distribution—IFNτ is only expressed in placental tissues of ungulate species and involved in pregnancy, whereas IFNω is found in many species and possesses the more canonical antiviral and immunomodulatory functions. IFNω and IFNα loci are expanded to include many subtypes in a number of species. (B) The chromosomal locations of human (top) and murine (bottom) IFNκ, IFNβ, and IFNϵ genes are depicted. The arrow direction indicates on which strand the gene is encoded: a left-to-right arrow depicts the forward or positive strand and a right-to-left arrow indicates the reverse or negative strand. IFNκ is the only subtype to contain an intron and is situated further away from the other type I IFNs, though its positioning relative to the other IFNs is different in mice and humans. IFNβ and IFNϵ roughly form the boundaries of the type I IFN locus, with the other type I IFNs falling between the two genes.

Figure 2

Summary of the Properties of IFNα and IFNβ in cancer and autoimmunity. Type I IFNs display both unique and overlapping properties in various disease states. In cancer, depending on the tumor and degree of metastases, both IFNα and IFNβ can contribute to tumor rejection by directly limiting tumor cell proliferation (depicted) but also through modulation of antitumor immune responses (not depicted). In certain cases, type I IFNs can induce PD-L1 expression on tumor cells, suppressing immune-mediated killing of the tumor. The factors that cause type I IFNs to exert detrimental effects remain poorly understood. In T1D, there is evidence that IFNα subtypes play an important role in pathogenesis. Forced expression of IFNα by pancreatic β-cells accelerated the onset and severity of T1D in a mouse model, and patients receiving IFNα therapy for treatment of other diseases have a higher incidence of T1D. Similarly, immune complex-driven activation of pDCs induces robust IFNα production, which may participate in initiation of SLE. Finally, IFNβ-derived therapeutics have well-established efficacy for treating MS patients. Though still largely debated, the mechanism of protection mediated by IFNβ is complex and possibly includes limiting cytokine production from pathogenic CD4⁺ T cells and augmenting IL-10 production in a number of cell types. β-cell, pancreatic β-cell; DC, dendritic cell; IL, interleukin; Mφ, macrophage; MS, multiple sclerosis; pDC, plasmacytoid dendritic cell; Rx, prescription drug; SLE, systemic lupus erythematosus; T1D, type I diabetes.