The Interferon (IFN)-stimulated GeneSp100Promoter Contains an IFN-γ Activation Site and an Imperfect IFN-stimulated Response Element Which Mediate Type I IFN Inducibility

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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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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Type I IFN Protects Permissive Macrophages fromLegionella pneumophilaInfection through an IFN-γ-Independent Pathway

The Journal of Immunology ◽

10.4049/jimmunol.173.2.1266 ◽

2004 ◽

Vol 173 (2) ◽

pp. 1266-1275 ◽

Cited By ~ 56

Author(s):

Giovanna Schiavoni ◽

Claudia Mauri ◽

Davide Carlei ◽

Filippo Belardelli ◽

Maddalena Castellani Pastoris ◽

...

Keyword(s):

Type I ◽

Type I Ifn ◽

Ifn Γ

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Free ISG15 as a dimer generates IL-1β-producing CD8α+ dendritic cells at the site of infection

10.1101/111658 ◽

2017 ◽

Author(s):

Anna Napolitano ◽

Annemarthe G. van der Veen ◽

Monique Bunyan ◽

Annabel Borg ◽

Svend Kjaer ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Independent Manner ◽

Molecular Determinants ◽

Live Parasite ◽

Ifn Γ ◽

Covalently Linked ◽

First Time

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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IL-12 and Type-I IFN Synergize for IFN-γ Production by CD4 T Cells, Whereas Neither Are Required for IFN-γ Production by CD8 T Cells after Listeria monocytogenes Infection

The Journal of Immunology ◽

10.4049/jimmunol.178.7.4498 ◽

2007 ◽

Vol 178 (7) ◽

pp. 4498-4505 ◽

Cited By ~ 59

Author(s):

Sing Sing Way ◽

Colin Havenar-Daughton ◽

Ganesh A. Kolumam ◽

Nural N. Orgun ◽

Kaja Murali-Krishna

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Type I ◽

Type I Ifn ◽

Listeria Monocytogenes Infection ◽

Ifn Γ

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The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds.

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.3951 ◽

1993 ◽

Vol 13 (7) ◽

pp. 3951-3963 ◽

Cited By ~ 114

Author(s):

Y Kanno ◽

C A Kozak ◽

C Schindler ◽

P H Driggers ◽

D L Ennist ◽

...

Keyword(s):

Gamma Interferon ◽

Chromosome 8 ◽

Alpha Subunit ◽

Upstream Region ◽

Lymphoid Tissues ◽

Type I ◽

Gamma Activation ◽

Response Element ◽

Ifn Gamma ◽

Activation Site

ICSBP, a member of the interferon regulatory factor family, is expressed predominantly in lymphoid tissues and is induced by gamma interferon (IFN-gamma). We have studied the genomic organization of the murine ICSBP gene and its 5' upstream region. The murine ICSBP gene (Icsbp) is present as a single copy on chromosome 8 and consists of nine exons. Transcription initiates at two juxtaposed sites downstream from the TATA and CAAT boxes and produces two species of ICSBP mRNA (3.0 and 1.7 kb), presumably by differential usage of poly(A)+ signals. A sequence from -175 to -155 was identified to be an IFN response region that conferred IFN-gamma induction upon a heterologous promoter in lymphoid cell line EL4. This region includes a motif, TTCNNGGAA, designated the palindromic IFN response element (pIRE), to which an IFN-gamma-inducible, cycloheximide-sensitive factor(s) binds. A similar palindromic motif was found in the upstream region of the murine IRF-1 gene, the IFN-gamma activation site of the guanylate-binding protein gene and the IFN-gamma-responsive region of the Fc receptor type I gene, all of which competed with the pIRE for factor binding in gel mobility shift assays. We show that the pIRE binding factor reacts with the antibody against the 91-kDa subunit of ISGF3 alpha recently shown to bind to the IFN-gamma activation site. These results suggest that this factor is related to the IFN-gamma activation factor and contains the 91-kDa subunit of ISGF3 alpha. Taken together, pIRE represents an IRE that is distinct from the classical IFN-stimulated response element and that is capable of conferring IFN-gamma induction through the binding of the 91-kDa ISGF3 alpha subunit (or an antigenically similar molecule).

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