Differential effects of type I and II interferons on myeloid cells and resistance to intracellular bacterial infections

Abstract

The type I and II interferons (IFNs) play important roles in regulating immune responses during viral and bacterial infections and in the context of autoimmune and neoplastic diseases. These two IFN types bind to distinct cell surface receptors that are expressed by nearly all cells to trigger signal transduction events and elicit diverse cellular responses. In some cases, type I and II IFNs trigger similar cellular responses, while in other cases, the IFNs have unique or antagonistic effects on host cells. Negative regulators of IFN signaling also modulate cellular responses to the IFNs and play important roles in maintaining immunological homeostasis. In this review, we provide an overview of how IFNs stimulate cellular responses. We discuss the disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections and provide an overview of models that have been proposed to account for these disparate effects. Mechanisms of antagonistic cross talk between type I and II IFNs are also introduced.

Figure 1. Canonical JAK/STAT signaling by the type I interferon receptor

Type I interferons such as IFN-β bind to cell surface IFNAR1 & 2 proteins to induce conformaitonal changes that cause the activation of IFNAR1 bound TYK2 and IFNAR2 bound JAK1 via transphosphorylation. Activated TYK2 and JAK1 phosphorylate residues in the cytosolic domains of the IFNAR to permit docking of cytosolic STAT-1 & 2 proteins. Upon docking, STAT-1 is phosphorylated at Y701 and STAT-2 at Y690 by TYK2 & JAK1. The phosphorylation event releases the pSTAT proteins and allows them to homo or heterodimerize. IRF9 is recruited to the pSTAT1/2 complex to create the trimeric ISGF3 complex. ISGF3 moves into the nucleus to bind ISRE elements in the promoters of interferon stimulated genes (ISGs). Type I IFN signaling also results in formation of some pSTAT1 homodimers that can bind GAS elements to regulate ISG expression. See text for additional details and references.

Figure 2. Major non-canonical signaling pathways activated by the type I interferon receptor

Ligand binding to the IFNAR and transphosphorylation of TYK2 & JAK1 can cause recruitment and phosphorylation of STAT proteins other than STAT1 and STAT2 (e.g. STAT-3). In addition, IFNα binding to the IFNαR can trigger phosphorylation of IRS-1 & 2 and VAV. STAT-3 or IRS-1/2 bind and stimulate PI3K upon phosphorylation to activate AKT. Activated AKT block proliferative responses and further signals via the NF-κB pathway. NF-κB activation regulates transcription of genes with pro-survival functions as well as genes that increase antigen processing and presentation. Phosphorylated VAV also activates NF-κB, as well as multiple MAP kinases (MAPK). MAPK activity can induce apoptosis, inhibit growth and prevent differentiation. See text for additional details and references.

Figure 3. Potentially detrimental effects of type I IFNs during intracellular bacterial infections

In wildtype mice, type I IFNs increase expression of the apoptotic factor TRAIL and SOCS proteins, while decreasing expression of certain inflammatory cytokines and chemokines and silencing transcription of ifngr1. These cellular changes increase apoptosis of certain immune cells, decrease recruitment of inflammatory cells, and decrease responsiveness to IFNγ. The absence of one or more of these effects may explain the increased susceptibility of mice that lack expression of the type I IFN receptor (IFNαR^−/−) to infections by diverse intracellular bacterial pathogens.