IFN-λ1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells

Dai, Jihong; Megjugorac, Nicholas J.; Gallagher, Grant; Yu, Raymond

doi:10.1182/blood-2008-09-179507

Cited by 107 publications

(134 citation statements)

References 54 publications

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“…In contrast to these investigations, some studies did propose direct effects of IFN-ls on monocytes, 32,33 DCs 34 and T cells. [35][36][37][38][39][40] We currently cannot explain the discrepancy in these observations in terms of whether IFN-ls influence, for example, monocytes or T cells. As we demonstrated, it seems that the preactivation with cell-specific stimuli or virus-mimicking agents could not confer any clear responsiveness to these cytokines on peripheral immune cells.…”

Section: Discussionmentioning

confidence: 94%

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

et al. 2009

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Interferon (IFN)-l1, -2 and -3 (also designated as interleukin (IL)-29, IL-28a and IL-28b) represent a new subfamily within the class II cytokine family. They show type I IFN-like antiviral and cytostatic activities in affected cells forming the basis for IFN-l1 therapy currently under development for hepatitis C infection. However, many aspects of IFN-ls are still unknown. This study aimed at identifying the target cells of IFN-ls within the immune system and the skin. Among skin cell populations, keratinocytes and melanocytes, but not fibroblasts, endothelial cells or subcutaneous adipocytes turned out to be targets. In contrast to these target cells, blood immune cell populations did not clearly respond to even high concentrations of these cytokines, despite an IFN-l receptor expression. Interestingly, immune cells expressed high levels of a short IFN-l receptor splice variant (sIFN-lR1/sIL-28R1). Its characterization revealed a secreted, glycosylated protein that binds IFN-l1 with a moderate affinity (K D 73 nM) and was able to inhibit IFN-l1 effects. Our study suggests that IFN-l therapy should be suited for patients with verrucae, melanomas and non-melanoma skin cancers, apart from patients with viral hepatitis, and would not be accompanied by immune-mediated complications known from type I IFN application.

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Section: Discussionmentioning

confidence: 94%

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

et al. 2009

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“…IL-29, expressed together with IFN-a by pDCs and macrophages in response to TLR ligands, was irrelevant in this process, despite its claimed role in T H 2 regulation. 33 We then decided to investigate the possible in vivo effects of nDer p 2-Conj in a murine prophylactic model of respiratory allergy aimed to assess the possible pro-T H 1 activity of the preparation. In nDer p 2-Conj-sensitized mice, IL-13 expression was decreased in the lungs and in in vitro allergen-stimulated, lungisolated mononuclear cells, suggesting a prevalent effect on the adaptive response.…”

Section: Discussionmentioning

confidence: 99%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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“…These effects can be direct on CD4 + T cells or indirect, via MDDC. Further, IFN-l1 secretion is itself Th2 cytokine responsive (11,12,(21)(22)(23). Recent studies also showed that IFN-l1 expression is reduced in alveolar macrophages and bronchial epithelial cells of rhinovirus-infected asthmatic individuals (24,25).…”

mentioning

confidence: 99%

“…Expression of IFN-l is restricted mainly to plasmacytoid dendritic cells and epithelial cells (8,9). Furthermore, expression of the IFN-l receptor (in which both chains are distinct from those used in either the type I or type II IFNRs) is almost completely restricted to immune cells and epithelial cells (9)(10)(11)(12). Thus, the restricted expression pattern of the IFN-l ligands and their receptor confers tight control on IFN-l responsiveness, in contrast to the situation with the ubiquitous type I IFNs.…”

mentioning

confidence: 99%

“…Two key contributing pathologies in asthma are the upregulation of Th2 responses and remodeling of the airway epithelial cells (26). Thus, the observed lack of a key regulator (IFN-l1) may be critical in asthmatic individuals, because it normally would be produced primarily by plasmacytoid dendritic cells and epithelial cells to both promote viral responsiveness and limit Th2 responses (8)(9)(10)(11).…”

mentioning

confidence: 99%

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Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

Siegel¹,

Eskdale²,

Gallagher³

2011

The Journal of Immunology

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The type III (λ) IFNs (IFN-λ1, IFN-λ2, and IFN-λ3) and their receptor are the most recently discovered IFN family. They are induced by viruses and mediate antiviral activity, but type III IFNs have an important, specific functional niche at the immune/epithelial interface, as well as in the regulation of Th2 cytokines. Their expression appears diminished in bronchial epithelial cells of rhinovirus-infected asthmatic individuals. We investigated the regulation of IFN-λ1 expression in human airway epithelial cells using reporter genes analysis, chromatin immunoprecipitation, small interfering RNA knockdown, and DNase footprinting. In this article, we define the c-REL/p65 NF-κB heterodimer and IRF-1 as key transcriptional activators and ZEB1, B lymphocyte-induced maturation protein 1, and the p50 NF-κB homodimer as key repressors of the IFN-λ1 gene. We further show that ZEB1 selectively regulates type III IFNs. To our knowledge, this study presents the first characterization of any type III IFN promoter in its native context and conformation in epithelial cells and can now be applied to understanding pathogenic dysregulation of IFN-λ1 in human disease.

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IFN-λ1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells

Abstract: IFN-1 (IL-29

Cited by 107 publications

References 54 publications

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

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