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Modulation of T cell responses by type I interferons

ABSTRACT: Type I interferons (IFNs) play a key role in linking the innate and adaptive immune responses. IFNs can have both positive and negative effects on the development of memory CD8+ T cells, but their contribution to the priming of naïve T cells is unclear. Using OT-I TCR transgenic T cells, we show strong effects on TCR-induced functional response when sensitized by IFN-β prior to their stimulation with cognate antigen. These effects are only seen in the absence of co-stimulation and at suboptimal TCR stimulation conditions. Pre-stimulation of naïve T cells inhibits certain TCR-mediated functions like cell proliferation and the induction of genes such as IFN-γ and IL-2. However, type I IFN does not influence the induction of other TCR-induced functions like the expression of the T cell activation marker CD25 and a number of other genes. IFN-mediated impairment of proliferation is due to the lack of IL-2 induction since it can be compensated by exogenous IL-2. Further analysis reveals an IFN-mediated inhibition of Ca2+ flux and ERK phosphorylation. In vivo studies confirm that pre-stimulation with IFNs inhibits early T cell responses, whereas long-term responses are positively affected. Our results reveal that IFN exerts negative effects on naïve T cells in a timely defined range under sub-optimal TCR stimulation conditions. These results highlight the importance of timing of immune-regulatory events and reveal a novel role for type I IFNs by shaping the immune response, such that T cells are not able to react until optimal stimulation is provided.

ORGANISM(S): Mus musculus

PROVIDER: GSE41381 | GEO | 2015/12/31

SECONDARY ACCESSION(S): PRJNA176720

REPOSITORIES: GEO

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Project description:This dataset details the time-dependent response of human Huh7 hepatoma cells to type I and type III IFN. Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize viral replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, microarray-based gene expression analysis is combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-M-NM-2 > IFN-M-NM-1 > IFN-M-NM-;3 > IFN-M-NM-;1 > IFN-M-NM-;2). This hierarchy resulted in widely varying numbers of differentially expressed genes when quantified using common statistical thresholds, even though individual IFNs did not appear to regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-M-NM-1. While stimulation with either IFN-M-NM-2 or IFN-M-NM-;s resulted in a similar long-lasting ISG induction, IFN-M-NM-1 signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-M-NM-1 suggest different roles for individual IFNs in the immune response, and help explain previously observed differences in antiviral activity. Huh7 cells were seeded into 6-well plates at the density of 3x10^5 cells/well and cultured overnight before stimulation with either 500 U/ml of IFN-M-NM-1 or IFN-M-NM-2, or 10 ng/ml of IFN-M-NM-;1, IFN-M-NM-;2, or IFN-M-NM-;3. Total RNA was harvested and isolated at 0.5, 1, 2, 4, 6, 12 and 24 hours post-incubation using RNeasy Mini Kit (Qiagen) following the Affymetrix GeneChip protocol of the Keck Affymetrix Resource facility at Yale University. IFN incubation at each time point was performed in duplicate. All subsequent processing, hybridization to the Illumina HumanHT-12 microarray, and quality control analyses were carried out by the Yale Center for Genome Analysis using standard protocols.

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Modulation of T cell responses by type I interferons

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