Type III Interferons, IL-28 and IL-29, Are Increased in Chronic HCV Infection and Induce Myeloid Dendritic Cell-Mediated FoxP3+ Regulatory T Cells

Dolganiuc, Angela; Kodys, Karen; Marshall, Christopher; Saha, Banishree; Zhang, Shuye; Bala, Shashi; Szabó, Gyöngyi

doi:10.1371/journal.pone.0044915

Cited by 64 publications

(64 citation statements)

References 25 publications

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“…2) IFN-λ may affect T-reg activity. IFN-λ are increased during the chronic stage of HCV and act on DC to stimulate CD4+FoxP3+ T-reg cells (55, 97), perhaps suppressing immune responses to HCV. A novel population of CD4 + FoxP3 + CD25 − T cells make IFN-λ and induce tolerance in a mouse EAE model (98), so potentially these tolerance-inducing populations of cells are induced in the infected WT mice but are diminished in the λR-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

IFN-λ Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

Misumi

Whitmire

2014

The Journal of Immunology

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IFN-lambda (IFN-λ) induces an antiviral state in many cell types and may contribute to the overall inflammatory environment following infection. Either of these effects may influence adaptive immune responses, but the role of type-3 interferons in the development of primary and memory T cell responses to infection has not been evaluated. Herein, we examined T cell responses to acute or persistent lymphocytic choriomeningitis virus (LCMV) infection in IFN-λR1-deficient mice. Following acute infection, we find that IFN-λR1-deficient mice produced normal levels of interferon, robust NK cell responses, but greater than normal CD4+ and CD8+ T cell responses compared to WT Balb/c mice. There were more T cells that were IL-7Rhi and, correspondingly, the IFN-λR-deficient mice showed a 2–3-fold increase in memory T cell number. The inhibitory effect of IFN-λR expression was independent of direct cytokine signaling into T cells. In contrast to acute infection, the IFN-λR-deficient mice generated markedly diminished T cell responses and had greater weight loss compared to WT mice when confronted with a highly disseminating variant of LCMV. These data indicate that IFN-λR limits T cell responses and memory following transient infection but augments T cell responses during persisting infection. Thus, the immune regulatory functions for IFN-λR are complex and vary with the overall inflammatory environment.

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Section: Discussionmentioning

confidence: 99%

IFN-λ Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

Misumi

Whitmire

2014

The Journal of Immunology

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“…However, its expression on hematopoietic cells remains controversial. This issue is discussed in more detail below, but it is generally believed that the main immune cells expressing IFN-λR1 are dendritic cells (DCs) (4, 7, 8). Most studies assessed the expression of IFN-λR1 by polymerase chain reaction (PCR), evaluating the mRNA level, which might not accurately reflect expression of the protein on cell surface.…”

Section: Tissue Tropism Of Type I Versus Type Iii Ifnsmentioning

confidence: 99%

“…Data from the chimp model of HCV infection demonstrated that type III IFNs were strongly induced upon HCV infection at the gene and protein level and correlated with ISG expression and viral load (28). In humans, while some studies associated the favorable IFN-λ3 CC allele with higher serum levels of IFN-λ (29), others demonstrated the reverse correlation (7). One report also found no difference in serum levels of IFN-λ between HCV treatment responders and non-responders (30).…”

Section: Mechanisms Underlying the Role Of Ifn-λ Polymorphisms In Hcvmentioning

confidence: 99%

Type III Interferons in Hepatitis C Virus Infection

Boisvert

Shoukry

2016

Front. Immunol.

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The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.

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“…Recent in vitro studies in mice [21] and humans [22], have suggested that IFN-λ promotes the generation of immature dendritic cells (DCs) with tolerogenic activity. IFN-λ-treated DCs specifically induced proliferation and expansion of regulatory T (T reg ) cells which play, a fundamental role in maintaining immune homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients

et al. 2016

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The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3–35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.

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Type III Interferons, IL-28 and IL-29, Are Increased in Chronic HCV Infection and Induce Myeloid Dendritic Cell-Mediated FoxP3+ Regulatory T Cells

Cited by 64 publications

References 25 publications

IFN-λ Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

IFN-λ Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

Type III Interferons in Hepatitis C Virus Infection

Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients

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