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Type I IFN signaling facilitates the development of IL-10-producing effector CD8⁺ T cells during murine influenza virus infection.

ABSTRACT: Recent evidence has suggested that IL-10-producing effector CD8⁺ T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8⁺ T cells are not completely defined. Here, we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8⁺ T cells during influenza virus infection in mice. We find that type I IFNs can enhance IL-27 production by lung APCs, thereby facilitating IL-10-producing CD8⁺ T-cell development through a CD8⁺ T-cell-nonautonomous way. Surprisingly, we also demonstrate that direct type I IFN signaling in CD8⁺ T cells is required for the maximal generation of IL-10-producing CD8⁺ T cells. Type I IFN signaling in CD8⁺ T cells, in cooperation with IL-27 and IL-2 signaling, promotes and sustains the expression of IFN regulatory factor 4 (IRF4) and B-lymphocyte-induced maturation protein-1 (Blimp-1), two transcription factors required for the production of IL-10 by effector CD8⁺ T cells. Our data reveal a critical role of the innate antiviral effector cytokines in regulating the production of a regulatory cytokine by effector CD8⁺ T cells during respiratory virus infection.

SUBMITTER: Jiang L

PROVIDER: S-EPMC5184847 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Type I IFN signaling facilitates the development of IL-10-producing effector CD8+ T cells during murine influenza virus infection.

Jiang Li L Yao Shuyu S Huang Su S Wright Jeffrey J Braciale Thomas J TJ Sun Jie J

European journal of immunology 20161109 12

Recent evidence has suggested that IL-10-producing effector CD8+ T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8+ T cells are not completely defined. Here, we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8+ T cells during influenza virus infection in mice. We fi ...[more]

PMID: 27701741

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Project description:CD4+ and CD8+ effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4+ T cells, including IL-17+ CD4+ T cells. Here, we further characterized the regulation of IL-10 expression via blockade of TNF signaling or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4+ T cell/monocyte cocultures led to increased percentages of IL-10+ cells in pro-inflammatory IL-17+, IFNγ+, TNFα+, GM-CSF+, and IL-4+ CD4+ T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10+ cell frequencies. TNF blockade also regulated IL-10 expression in CD4+ T cells upon antigenic stimulation. Using time course experiments in whole peripheral blood mononuclear cell (PBMC) cultures, we show that TNF blockade maintained, rather than increased, IL-10+ cell frequencies in both CD4+ and CD8+ T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4+ or CD8+ T cell subpopulations. We show that TNF blockade acts directly on effector CD4+ T cells, in the absence of monocytes or CD4+ CD25highCD127low regulatory T cells and independently of IL-27, resulting in higher IL-10+ frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10+ CD4+ T cell frequencies in 3-day CD4+ T cell/monocyte cocultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together, these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10+ phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy.

Dataset Information

Type I IFN signaling facilitates the development of IL-10-producing effector CD8⁺ T cells during murine influenza virus infection.

Publications

Type I IFN signaling facilitates the development of IL-10-producing effector CD8<sup>+</sup> T cells during murine influenza virus infection.

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