Cutting Edge: Type I IFN Reverses Human Th2 Commitment and Stability by Suppressing GATA3

Huber, Jonathan; Ramos, Hilario J.; Gill, Michelle A.; Farrar, J. David

doi:10.4049/jimmunol.1000469

Cited by 120 publications

(127 citation statements)

References 34 publications

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“…2B). There is evidence that IFN-a and IFN-b can inhibit Th2 immune responses, including eosinophilia (36) and cytokine secretion by committed Th2 cells (26,27). To the best of our knowledge, the current investigation is the first report examining the effects of IFN-a and IFN-b on RVspecific immune responses in humans.…”

Section: Discussionmentioning

confidence: 86%

“…Type-I IFNs (IFN-ab) play a well-established role in early innate immune defense against a wide range of viral pathogens (23). Experimental evidence also suggests that IFN-ab can modulate adaptive immunity to many viruses, supporting the polarization and effector function of Th1 cells (24) and Th17 cells (25), while inhibiting Th2 commitment and secretion of potentially malad-aptive Th2 cytokines (26,27). The extent to which these observations hold true in relation to RV has not been studied, but may be highly relevant to the pathophysiology of asthma where IFNab synthesis appears to be deficient, and where a Th2 or Th17 response to the virus might worsen eosinophilic or neutrophilic airway inflammation, respectively.…”

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confidence: 99%

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Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

The Journal of Immunology

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Human rhinoviruses (RV) cause only minor illness in healthy individuals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy individuals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p < 0.01), and IL-13 (p < 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma; deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

The Journal of Immunology

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“…IFNs and IL-4 exhibit antagonistic actions against each other in the differentiation of Th1 versus Th2 cells, IgE production, and the expression of class II MHC, IL-1R, Fc epsilon receptor II/CD23, and IFN regulatory factors (IRFs) [12][13][14][15][16][17]. Among these, the counterregulation of CD23 by IFNs and IL-4 has been widely reported.…”

Section: Introductionmentioning

confidence: 99%

“…While IFN-g induces STAT1 activation, leading to the formation of STAT1 homodimer, IFN-a induces the formation of IFN-stimulated gene factor 3 (ISGF3; STAT1:STAT2:p48) as well [9,10]. It has been recently shown that STAT4 or STAT6 can also be activated by IFN-a in certain cell types, such as lymphoid and endothelial cells [11,12].IFNs and IL-4 exhibit antagonistic actions against each other in the differentiation of Th1 versus Th2 cells, IgE production, and the expression of class II MHC, IL-1R, Fc epsilon receptor II/CD23, and IFN regulatory factors (IRFs) [12][13][14][15][16][17]. Among these, the counterregulation of CD23 by IFNs and IL-4 has been widely reported.…”

mentioning

confidence: 99%

Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

Kim¹,

Lee²

2010

Eur J Immunol

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IFN-a and IL-4 induce Th1 and Th2 responses, respectively, and often display antagonistic actions against each other. To elucidate the molecular mechanism of counter-regulation, we have investigated the signal interception by IFN-a and IL-4, employing a human B-cell line Ramos, sensitive to both cytokines. In these cells, IFN-a effectively inhibited IL-4-induced Fc epsilon receptor II (CD23) expression, whereas IL-4 suppressed IFN-amediated IRF7 expression. The counter-regulatory action by IL-4 and IFN-a proceeded with a delayed kinetics requiring 4 h. Notably, IFN-a did not affect the IL-4-induced tyrosine phosphorylation of STAT6, but induced a time-dependent cytoplasmic accumulation of phosphotyrosine(pY)-STAT6 and a corresponding decrease in nuclear pY-STAT6. By confocal analysis and co-immunoprecipitation assays, we demonstrated the colocalization and molecular interaction of IL-4-induced pY-STAT6 with IFN-a-induced pY-STAT2:p48 in the cytosol. In addition, the over-expression of STAT2 or STAT6 induced the concomitant cytosolic accumulation of pY-STAT6 or pY-STAT2, leading to the suppression of IL-4-induced CD23 or IFN-a-induced IRF7 gene expression, respectively. Our data suggest that the signals ensued by IFN-a and IL-4 induce cytoplasmic sequestration of IL-4-activated STAT6 and IFN-a-activated STAT2:p48 in B cells through the formation of pY-STAT6:pY-STAT2:p48 complex, which provides a novel mechanism by which IFN-a and IL-4 cross-regulate their signaling into the nucleus.Keywords: Counter-regulation . Cytosolic retention . IFN-a signaling . IL-4 signaling pY-STAT6:pY-STAT2:p48 complex Supporting Information available online IntroductionIn the innate and the adaptive immune system, cytokines act as key regulators for the activation, proliferation, differentiation, development, and death of immune cells [1,2]. IL-4 is an immunomodulatory cytokine secreted by activated Th2 lymphocytes, basophils, and mast cells [3]. Its pleiotropic functions include the differentiation of Th2 cells, B-cell activation, immunoglobulin isotype switching, the inhibition of Th1 differentiation, and the development of allergic diseases. In hematopoietic cells, responses to IL-4 are mediated by the receptor complex composed of IL-4 receptor (IL-4R) a and common g-chain (gc). Once these receptor chains are heterodimerized upon IL-4 binding, the receptor-associated Jaks (Jak 1/3) are activated, inducing phosphorylation of a tyrosine residue within the cytoplasmic tail of IL-4Ra [3]. The phosphotyrosine (pY) 461 motif generated on the receptor then acts as a docking site to recruit STAT6, leading to the tyrosine phosphorylation of STAT6 by Jaks. Subsequently, phosphorylated STAT6 departs from the receptor, dimerizes, and translocates into the nucleus, where it turns on the expression of IL-4 target genes [3,4]. The IL-4-induced STAT6 activity is shown to be essential for the establishment of distal promoter activity for GATA3 transcription in developing Th2 cells [5]. IFNs are widely expressed cytokines with multiple biological act...

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“…In the current study, we examine the effects of inflammatory cytokines on determining the susceptibility of human CD8 T cells to post-activation cell death. We have focused specifically on the response of human T cells, because there are some distinctions between the mechanisms by which inflammatory cytokines affect the biology of human as compared with mouse effector T cells (20). Activated CD8 T cells express IL-12R␤1 and IL-12R␤2 (21).…”

mentioning

confidence: 99%

Inflammatory Cytokines Determine the Susceptibility of Human CD8 T Cells to Fas-mediated Activation-induced Cell Death through Modulation of FasL and c-FLIPS Expression

Rossum

Krall

Escalante

et al. 2011

Journal of Biological Chemistry

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Cutting Edge: Type I IFN Reverses Human Th2 Commitment and Stability by Suppressing GATA3

Abstract: Material

Cited by 120 publications

References 34 publications

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

Inflammatory Cytokines Determine the Susceptibility of Human CD8 T Cells to Fas-mediated Activation-induced Cell Death through Modulation of FasL and c-FLIPS Expression

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