Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment

Abstract

Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models. In both viral infection and tumor models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced Treg associated activation antigens. LCMV-specific CD8+ T cells and tumor infiltrating lymphocytes from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral and antitumor IFN-γ and TNF-α. In chronic viral model, the numbers of antiviral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs during chronic infection, and higher tumor burden than the WT controls. The enhanced activated phenotype was evident through transcriptome analysis of IFNARfl/flxFoxp3YFP-Cre mice Tregs during infection demonstrated differential expression of a unique gene signature characterized by elevated levels of genes involved in suppression and decreased levels of genes mediating apoptosis. Thus, IFN signaling in Tregs is beneficial to host resulting in a more effective antiviral response and augmented antitumor immunity.

Rapid expansion of Treg cells protects from collateral colitis following a viral trigger

“…Type I IFNs support a vast array of protective host defense mechanisms including the restriction of viral replication 14 , NK cell cytotoxicity 21 , and survival of cytotoxic T cells 22 . In addition, recent studies revealed that type I IFN receptor (IFNAR) engagement also impacts on Treg cell activation and proliferation under inflammatory conditions 23,24 . However, how viral infections and the concomitant type I IFN response might affect the ability of Treg cells to maintain peripheral tolerance has not been addressed.…”

Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice

“…Comparable differential, seemingly conflicting effects have already been described with regard to regulatory T cells. While type I IFN signaling attenuates Treg function in the tumor microenvironment or during viral infection, IFNAR signaling promotes Treg function in autoimmunity, including EAE [49][50][51].…”

Key candidate genes of STAT1 and CXCL10 in melanoma identified by integrated bioinformatical analysis

“…Studies have shown that the Type I interferon signalling pathway plays a predominant role in the immune response to infectious and tumour environments . The immune response is mediated by Type I interferons (IFNs), which are members of the cytokine family including IFN‐α and IFN‐β .…”

“…Studies have shown that the Type I interferon signalling pathway plays a predominant role in the immune response to infectious and tumour environments. 16 The immune response is mediated by Type I interferons (IFNs), which are members of the cytokine family including IFN-α and IFN-β. 17 IFNs bind to the heterodimeric receptor IFN-α/β receptor (IFNAR), thereby activating Janus kinases (JAK) to induce the phosphorylation of signal transducer and activator of transcription (STAT).…”