Immune cells communicate with one another in many different ways, including through the production of cytokines. Cytokines are proteins that cells expel, or secrete, that can travel to other cells in the body, bind to receptor proteins on the cell surface, and relay a message. One important class of cytokines is interferons (IFNs), which play a vital role in protecting cells against viral infections. In fact, the name “interferon” reflects the fact that these cytokines were discovered based upon their ability to interfere with the production of viral particles. IFNs have been divided into three groups based upon 1) their sequences and 2) the receptor proteins to which they bind on receiving cells. In spite of belonging to the same family of proteins, different types of IFNs can have drastically different effects on cells.

Type I interferons

 The most ubiquitous and well-studied members of the type I interferon family are IFN-α, of which there are 13 subtypes in humans, and IFN-β, of which there is only one. These IFNs can be produced by many different cell types in response to viral infections. Other members of the type I IFN family exist, but these are either cell-type or species specific; for example, IFN-δ has only been found in the early development of pigs.

Type I IFNs are produced by cells in response to a viral infection. Specifically, cells sense the presence of invading pathogens, like viruses, because they carry pathogen-associated molecular patterns (PAMPs). These PAMPs are pathogen-specific molecules, such proteins in the exterior envelope of a virus, that flag the pathogen as foreign and potentially dangerous. In turn, proteins on our cells called pattern-recognition receptors (PRRs) recognize and bind these PAMPs in a lock and key fashion, and this binding induces our cells to enact anti-pathogenic mechanisms aimed at preventing viral spread (Figure 1).

A key player in this PAMP-induced anti-pathogenic campaign is type I IFN. PRR-PAMP binding induces the production of type I IFNs, which are released from virus-sensing cells into the extracellular environment. The IFNs can then act on the IFN-producing cell and its neighbors to communicate anti-viral messages and initiate antiviral defenses. Specifically, type I IFNs bind to type I IFN receptors on cell surfaces and activate intracellular proteins (i.e. JAKs and STATs), which ultimately alters gene expression. The IFN-induced genes largely function to accomplish three tasks: 1) limit viral spread, 2) modulate the innate immune response to the infection, and 3) activate the adaptive immune system. For example, type I IFNs can activate a protein called dsRNA-activated protein kinase (PKR), which impedes protein production inside cells and thus prevents viruses from replicating and spreading. Another example is the IFN-induced protein MxA, which binds viral particles inside infected cells and ultimately inhibits their spread. In sum, type I IFN-induced responses can directly prevent viral spread and can innervate the immune system to accomplish viral eradication.

 Type II interferons

IFN-γ is the only type II interferon. Unlike type I IFNs, which are produced by many different cell types in direct response to viral infection, IFN-γ is primarily produced by activated immune cells. Specifically, natural killer (NK) cells, natural killer T (NKT) cells, CD8+, and CD4+ T cells produce IFN-γ following receptor activation, antigen binding, and/or cytokine stimulation. Once secreted, IFN-γ can bind to its receptors present on many different cell types and induce a variety of anti-viral mechanisms.

Like type I IFNs, IFN-γ can directly inhibit viral spread; however, many of the major anti-viral effects of IFN-gare more indirect. For example, IFN-gcan increase the expression of MHC class I and II. MHC proteins compose complexes that allow cells to display antigens, or immunogenic peptides, on their surface and alert the immune system to an infection. In this way, IFN-γ enhances the ability of adaptive immune cells to recognize virally infected cells and eradicate them, thereby limiting viral spread. Furthermore, immune cell-derived IFN-γ can activate macrophages to enhance their ability to engulf, or phagocytose, virally infected cells. The differentiation of anti-pathogenic CD4Th1 cells is also favored by the presence of IFN-γ, while the development of immune-inhibitory regulatory T-cells is suppressed by the presence of IFN-γ. By modulating the T-cell repertoire in this way, IFN-γ can support a more active immune system capable of combatting pathogenic invaders. In these way and many more, IFN-γ production can limit the spread of pathogens like viruses throughout the body.

Type III interferons

Type III IFNs, also known as the IFN-λs, are similar to type I IFNs in many ways. Like type I IFNs, type III IFNs have very similar anti-viral effects, can be produced by many types of immune cells and virally infected cells, and are generated following the recognition of PAMPs by PRRs. However, type III IFNs have more limited applicability. In contrast to type I IFN receptors, which are present on many cells types and allow wide-ranging responses to type I IFNs, type III IFN receptors are largely restricted to cells with a high susceptibility to pathogenic encounters, such as the cells that line our intestines and lungs. Of note, although type I IFNs and type III IFNs induce many common antiviral mechanisms, they also exhibit non-overlapping functions specific to each type.

Figure 1. Interferon responses in activated cells. When a cell is exposed to PAMPs, either in the extracellular environment or inside the cell following pathogenic infection, PRRs can bind and induce an intracellular signaling cascades that result in the production of type I and type III interferons. These IFN molecules can act on the pathogen-sensing cell and its neighbors to induce a slew of gene expression changes, including those that directly inhibit viral replication (left). Additionally, when certain immune cells (like NK, NKT, CD8+, and CD4+ T cells) become activated, as through cytokine or antigen stimulation, they can secrete the type II IFN, IFN-γ. This molecule can act on the producing immune cells as well as neighboring virally infected cells to inhibit viral spread, as by promoting MHC expression and antigen presentation.

 

Featured image credit: Nevit Dilmen WikiMedia Commons CC BY-SA 3.0

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