Subtypes of type <scp>I IFN</scp> differentially enhance cytokine expression by suboptimally stimulated <scp>CD</scp>4<sup>+</sup><scp>T</scp> cells

Hillyer, Philippa; Raviv, Nataly; Gold, Doria M.; Dougherty, Danielle; Liu, Jie; Johnson, Teresa R.; Graham, Barney S.; Rabin, Ronald L.

doi:10.1002/eji.201243288

Cited by 13 publications

(10 citation statements)

References 68 publications

(80 reference statements)

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“…The roles of type I and III IFNs in limiting RSV infection are not well defined. IFNs affect adaptive immunity, either beneficially, by enhancing CD4 T cell polarization toward the Th1 phenotype (45) or by increasing expression of IFN-␥ by Th1 CD4 T cells (46), or adversely, by enhancing IL-4 expression by Th2 memory cells (46) or suppressing T cell proliferation (47). In infected cells, RSV NS1 and NS2 proteins efficiently suppress IFN expression and signaling (48), so the potential roles of type I and type III IFNs are likely limited to inducing or enhancing the intrinsic antiviral states (49) of neighboring cells.…”

Section: Discussionmentioning

confidence: 99%

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Hillyer

Shepard

Uehling

et al. 2018

J Virol

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Respiratory syncytial virus (RSV) infects small foci of respiratory epithelial cells via infected droplets. Infection induces expression of type I and III interferons (IFNs) and proinflammatory cytokines, the balance of which may restrict viral replication and affect disease severity. We explored this balance by infecting two respiratory epithelial cell lines with low doses of recombinant RSV expressing green fluorescent protein (rgRSV). A549 cells were highly permissive, whereas BEAS-2B cells restricted infection to individual cells or small foci. After infection, A549 cells expressed higher levels of IFN-β-, IFN-λ-, and NF-κB-inducible proinflammatory cytokines. In contrast, BEAS-2B cells expressed higher levels of antiviral interferon-stimulated genes, pattern recognition receptors, and other signaling intermediaries constitutively and after infection. Transcriptome analysis revealed that constitutive expression of antiviral and proinflammatory genes predicted responses by each cell line. These two cell lines provide a model for elucidating critical mediators of local control of viral infection in respiratory epithelial cells. Airway epithelium is both the primary target of and the first defense against respiratory syncytial virus (RSV). Whether RSV replicates and spreads to adjacent epithelial cells depends on the quality of their innate immune responses. A549 and BEAS-2B are alveolar and bronchial epithelial cell lines, respectively, that are often used to study RSV infection. We show that A549 cells are permissive to RSV infection and express genes characteristic of a proinflammatory response. In contrast, BEAS-2B cells restrict infection and express genes characteristic of an antiviral response associated with expression of type I and III interferons. Transcriptome analysis of constitutive gene expression revealed patterns that may predict the response of each cell line to infection. This study suggests that restrictive and permissive cell lines may provide a model for identifying critical mediators of local control of infection and stresses the importance of the constitutive antiviral state for the response to viral challenge.

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Section: Discussionmentioning

confidence: 99%

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Hillyer

Shepard

Uehling

et al. 2018

J Virol

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“…Conversely, IL-4 or IL-13 may induce expression of SOCS1, which suppresses signaling of STAT1 and STAT2 (Hebenstreit et al, 2005; Hebenstreit et al, 2003). Once T cells are polarized, however, type I IFNs enhance expression of IL-4 (Hillyer et al, 2013), and may therefore adversely amplify type 2 inflammation associated with a viral respiratory infection.…”

Section: Discussionmentioning

confidence: 99%

Respiratory syncytial virus infection induces a subset of types I and III interferons in human dendritic cells

et al. 2017

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Whether respiratory syncytial virus (RSV) induces severe infantile pulmonary disease may depend on viral strain and expression of types I and III interferons (IFNs). These IFNs impact disease severity by inducing expression of many anti-viral IFN-stimulated genes (ISGs). To investigate the impact of RSV strain on IFN and ISG expression, we stimulated human monocyte-derived DCs (MDDCs) with either RSV A2 or Line 19 and measured expression of types I and III IFNs and ISGs. At 24h, A2 elicited higher ISG expression than Line 19. Both strains induced MDDCs to express genes for IFN-β, IFN-α1, IFN-α8, and IFN-λ1–3, but only A2 induced IFN-α2, -α14 and -α21. We then show that IFN-α8 and IFN-α14 most potently induced MDDCs and bronchial epithelial cells (BECs) to express ISGs. Our findings demonstrate that RSV strain may impact patterns of types I and III IFN expression and the magnitude of the ISG response by DCs and BECs.

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“…5, F–H ). The basis of these differences is unclear and may relate to differences in IFN-α subtypes used as the potencies of the 12 IFN-αs differ ( Hillyer et al, 2013 ), stimulation conditions, and/or differences in IFNAR signaling of IFN-α and IFN-β ( de Weerd et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling

Holmes¹,

Suto²,

Lee³

et al. 2015

Journal of Experimental Medicine

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Holmes et al. demonstrate that the protein tyrosine phosphatase PEP (PTPN22 in humans) associated with lupus and other autoimmune diseases, inhibits IFN-α receptor signaling in mice. PEP-deficient hematopoietic progenitors demonstrate increased IFNAR signaling, IFN-inducible gene expression and proliferation. PEP-deficient mice treated with IFN-α exhibit lupus-like disease and profound defects in hematopoiesis, resulting in cytopenia.

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Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4⁺T cells

Abstract: Human type I interferons (IFNs

Cited by 13 publications

References 68 publications

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Respiratory syncytial virus infection induces a subset of types I and III interferons in human dendritic cells

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling

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Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4+T cells

Abstract: Human type I interferons (IFNs

Cited by 13 publications

References 68 publications

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Differential Responses by Human Respiratory Epithelial Cell Lines to Respiratory Syncytial Virus Reflect Distinct Patterns of Infection Control

Respiratory syncytial virus infection induces a subset of types I and III interferons in human dendritic cells

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling

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Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4⁺T cells