Type I IFN Induces IL-10 Production in an IL-27–Independent Manner and Blocks Responsiveness to IFN-γ for Production of IL-12 and Bacterial Killing inMycobacterium tuberculosis–Infected Macrophages

AbstractISG15 is strongly induced after type I IFN stimulation producing a protein comprised of two ubiquitin-like domains. Intracellularly, ISG15 can be covalently linked and modify the function of target proteins (ISGylation). In addition, free unconjugated ISG15 can be released from cells. We found that ISG15 is released in the serum of Toxoplasma gondii infected mice early after infection in a type-I IFN independent manner. Once in the extracellular space, free ISG15 forms dimers and enhances the release of key cytokines involved in the immune response to the parasite: IL-12, IFN-γ, and IL-1β. Its action is dependent on an actively invading and replicating live parasite. ISG15 induces an increase of IL-1β later during infection by leading to increased IL-1β producing CD8α+ dendritic cells at the site of infection. Here, we define for the first time the molecular determinants of active free ISG15 and link ISG15 to IL-1β production by CD8α+ dendritic cells. Thus we define ISG15 as a novel secreted modulator of the cytokine response during Toxoplasma infection.

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STING: a master regulator in the cancer-immunity cycle

Molecular Cancer ◽

10.1186/s12943-019-1087-y ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 28

Author(s):

Yuanyuan Zhu ◽

Xiang An ◽

Xiao Zhang ◽

Yu Qiao ◽

Tongsen Zheng ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Negative Effects ◽

Independent Manner ◽

Adaptive Immune ◽

Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

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IL-15 and IFN-γ signal through the ERK pathway to inhibit HCV replication, independent of type I IFN signaling

Cytokine ◽

10.1016/j.cyto.2018.06.006 ◽

2019 ◽

Vol 124 ◽

pp. 154439 ◽

Cited By ~ 3

Author(s):

Fatemeh Vahedi ◽

Amanda J. Lee ◽

Susan E. Collins ◽

Marianne V. Chew ◽

Evan Lusty ◽

...

Keyword(s):

Type I ◽

Erk Pathway ◽

Type I Ifn ◽

Ifn Γ

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Deficiency of the AIM2–ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-γ Immunity in Mycobacterial Infection

The Journal of Immunology ◽

10.4049/jimmunol.1701177 ◽

2017 ◽

Vol 200 (3) ◽

pp. 1016-1026 ◽

Cited By ~ 9

Author(s):

Shanshan Yan ◽

Hongbo Shen ◽

Qiaoshi Lian ◽

Wenlong Jin ◽

Ronghua Zhang ◽

...

Keyword(s):

Mycobacterial Infection ◽

Type I ◽

Type I Ifn ◽

Ifn Γ

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IL-6 Produced by Type I IFN DC Controls IFN-γ Production during the MLR by Blocking the Suppressive Effect of Regulatory T Cells.

Blood ◽

10.1182/blood.v104.11.3797.3797 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3797-3797

Author(s):

Olivier Detournay ◽

Naima Mazouz ◽

Michel Goldman ◽

Michel Toungouz

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Mrna Level ◽

Suppressive Effect ◽

Poly I:C ◽

Type I ◽

Type I Ifn ◽

Effector Cells ◽

Gm Csf ◽

Ifn Γ

Abstract The dendritic cell family is composed of different subsets able to differentially govern the immune response. Their potent antigen presenting properties make them an attractive candidate for immunization against pathogens or cancer. In that setting, the recently characterized type I IFN DCs present interesting features including a higher expression of molecules involved in antigen presentation and the ability to trigger both the cellular and humoral arms of the immune responses. In view of the pivotal role of regulatory T cells in limiting the effectiveness of effector cells, we analyzed the interactions between these cells and type I IFN DC. DC generated from monocytes in the presence of IFN-β and IL-3 (DCI3) were activated by the maturation agent poly I:C and compared with the classical myeloid DC generated in the presence of GM-CSF and IL-4 (DCG4). Despite the release of lower amounts of IL-12 after maturation, DCI3 were able to induce a higher IFN-γ production by T lymphocytes during the MLR. Analysis at the mRNA level disclosed that DCI3 over transcribed the IL-6 gene leading to the release of high amounts of the protein both after the maturation process and during the MLR itself. Neutralization of IL-6 revealed that this cytokine specifically contributed to the IFN-γ release induced by DCI3. Finally, depletion of CD25+ T cells prior to the MLR identified these cells as a target for IL-6. We conclude from these results that DCI3 are endowed with the unique property of blocking the suppressive effect of regulatory T cells through high IL-6 production during the MLR. This novel mechanism of T cell control is relevant for the use of this DC type in vaccination strategies.

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Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

Infection and Immunity ◽

10.1128/iai.01176-10 ◽

2011 ◽

Vol 79 (5) ◽

pp. 2112-2119 ◽

Cited By ~ 21

Author(s):

Anne-Danielle C. Chessler ◽

Kacey L. Caradonna ◽

Akram Da'dara ◽

Barbara A. Burleigh

Keyword(s):

Trypanosoma Cruzi ◽

Parasite Burden ◽

Host Susceptibility ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Content Type ◽

Type I Ifns ◽

Ifn Γ ◽

The Impact

ABSTRACTTrypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimentalT. cruziinfection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR−/−) 129sv/ev mice were infected with two differentT. cruzistrains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection againstT. cruzi. In contrast, under conditions of lethalT. cruzichallenge, WT mice succumbed to infection whereas IFNAR−/−mice were ultimately able to control parasite growth and survive.T. cruziclearance in and survival of IFNAR−/−mice were accompanied by higher levels of IFN-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ and other cytokines/chemokines remains to be fully determined in the context ofT. cruziinfection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-γ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

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Virus Multiplicity of Infection Affects Type I Interferon Subtype Induction Profiles and Interferon-Stimulated Genes

Journal of Virology ◽

10.1128/jvi.01727-15 ◽

2015 ◽

Vol 89 (22) ◽

pp. 11534-11548 ◽

Cited By ~ 17

Author(s):

Luna A. Zaritsky ◽

Jacquelyn R. Bedsaul ◽

Kathryn C. Zoon

Keyword(s):

Distinct Type ◽

Gene Induction ◽

Viral Diseases ◽

Type I ◽

Multiplicity Of Infection ◽

The Novel ◽

Type I Ifn ◽

Independent Manner ◽

Type I Ifns ◽

In Cells

ABSTRACTType I interferons (IFNs) are induced upon viral infection and important mediators of innate immunity. While there is 1 beta interferon (IFN-β) protein, there are 12 different IFN-α subtypes. It has been reported extensively that different viruses induce distinct patterns of IFN subtypes, but it has not been previously shown how the viral multiplicity of infection (MOI) can affect IFN induction. In this study, we discovered the novel finding that human U937 cells infected with 2 different concentrations of Sendai virus (SeV) induce 2 distinct type I IFN subtype profiles. Cells infected at the lower MOI induced more subtypes than cells infected at the higher MOI. We found that this was due to the extent of signaling through the IFN receptor (IFNAR). The cells infected at the lower viral MOI induced the IFNAR2-dependent IFN-α subtypes 4, 6, 7, 10, and 17, which were not induced in cells infected at higher virus concentrations. IFN-β and IFN-α1, -2, and -8 were induced in an IFNAR-independent manner in cells infected at both virus concentrations. IFN-α5, -14, -16, and -21 were induced in an IFNAR-dependent manner in cells infected at lower virus concentrations and in an IFNAR-independent manner in cells infected at higher virus concentrations. These differences in IFN subtype profiles in the 2 virus concentrations also resulted in distinct interferon-stimulated gene induction. These results present the novel finding that different viral MOIs differentially activate JAK/STAT signaling through the IFNAR, which greatly affects the profile of IFN subtypes that are induced.IMPORTANCEType I IFNs are pleiotropic cytokines that are instrumental in combating viral diseases. Understanding how the individual subtypes are induced is important in developing strategies to block viral replication. Many studies have reported that different viruses induce distinct type I IFN subtype profiles due to differences in the way viruses are sensed in different cell types. However, we report in our study the novel finding that the amount of virus used to infect a system can also affect which type I IFN subtypes are induced due to the extent of activation of certain signaling pathways. These distinct IFN subtype profiles in cells infected at different MOIs are correlated with differences in interferon-stimulated gene induction, indicating that the same virus can induce distinct antiviral responses depending on the MOI. Because type I IFNs are used as therapeutic agents to treat viral diseases, understanding their antiviral mechanisms can enhance clinical treatments.

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IL-6 Produced by Type I IFN DC Controls IFN-γ Production by Regulating the Suppressive Effect of CD4+ CD25+ Regulatory T Cells

Human Immunology ◽

10.1016/j.humimm.2005.01.012 ◽

2005 ◽

Vol 66 (5) ◽

pp. 460-468 ◽

Cited By ~ 20

Author(s):

Olivier Detournay ◽

Naima Mazouz ◽

Michel Goldman ◽

Michel Toungouz

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Suppressive Effect ◽

Type I ◽

Type I Ifn ◽

Ifn Γ

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Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

Journal of Virology ◽

10.1128/jvi.01148-17 ◽

2017 ◽

Vol 91 (21) ◽

Cited By ~ 18

Author(s):

Rui Zhang ◽

Aotian Xu ◽

Chao Qin ◽

Qiong Zhang ◽

Shifan Chen ◽

...

Keyword(s):

Pseudorabies Virus ◽

Type I Interferon ◽

Antiviral Drug ◽

Ectopic Expression ◽

Interferon Response ◽

Type I ◽

Type I Ifn ◽

Lysosomal Degradation ◽

Independent Manner ◽

Strong Inhibitor

ABSTRACT Alphaherpesviruses that establish persistent infections rely partly on their ability to evade host antiviral responses, notably the type I interferon (IFN) response. However, the mechanisms employed by alphaherpesviruses to avoid this response are not well understood. Pseudorabies virus (PRV) is an economically important pathogen and a useful model system for studying alphaherpesvirus biology. To identify PRV proteins that antagonize type I IFN signaling, we performed a screen by using an IFN-stimulated response element reporter in the swine cell line CRL. Unexpectedly, we identified the dUTPase UL50 as a strong inhibitor. We confirmed that UL50 has the ability to inhibit type I IFN signaling by performing ectopic expression of UL50 in cells and deletion of UL50 in PRV. Mechanistically, UL50 impeded type I IFN-induced STAT1 phosphorylation, likely by accelerating lysosomal degradation of IFN receptor 1 (IFNAR1). In addition, this UL50 activity was independent of its dUTPase activity and required amino acids 225 to 253 in the C-terminal region. The UL50 encoded by herpes simplex virus 1 (HSV-1) also possessed similar activity. Moreover, UL50-deleted PRV was more susceptible to IFN than UL50-proficient PRV. Our results suggest that in addition to its dUTPase activity, the UL50 protein of alphaherpesviruses possesses the ability to suppress type I IFN signaling by promoting lysosomal degradation of IFNAR1, thereby contributing to immune evasion. This finding reveals UL50 as a potential antiviral target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that this alphaherpesvirus could utilize its encoded dUTPase UL50 to induce IFNAR1 degradation and inhibit type I IFN signaling in an enzymatic activity-independent manner. Our finding reveals a mechanism employed by an alphaherpesvirus to evade the immune response and indicates that UL50 is an important viral protein in pathogenesis and is a potential target for antiviral drug development.

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