Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting 'FAST' regulatory dendritic cells

D Rojas-Canales, Ravi Krishnan, Claire Jessup, P Coates

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    Interferon (IFN)-γ is a cytokine with immunomodulatory properties, which has been shown previously to enhance the generation of tolerogenic dendritic cells (DC) when administered early ex vivo in 7-day monocyte-derived DC culture. To generate tolerogenic DC rapidly within 48h, human monocytes were cultured for 24h with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence (IFN-γ-DC) or absence of IFN-γ (500U/ml) (UT-DC). DC were matured for 24h with TNF-α and prostaglandin E 2 (PGE 2). DC phenotype, signal transducer and activator of transcription-6 (STAT-6) phosphorylation and promotion of CD4 +CD25 +CD127 neg/lowforkhead box P3 (FoxP3) hi T cells were analysed by flow cytometry. DC nuclear factor (NF)-κB transcription factor reticuloendotheliosis viral oncogene homologue B (RELB) and IL-12p70 protein expression were also determined. Phenotypically, IFN-γ-DC displayed reduced DC maturation marker CD83 by 62% and co-stimulation molecules CD80 (26%) and CD86 (8%). IFN-γ treatment of monocytes inhibited intracellular STAT6, RELB nuclear translocation and IL-12p70 production. IFN-γ-DC increased the proportion of CD4 +CD25 +CD127 neg/lowfoxp3 hi T cells compared to UT-DC from 12 to 23%. IFN-γ-DC primed T cells inhibited antigen-specific, autologous naive T cell proliferation by 70% at a 1:1 naive T cells to IFN-γ-DC primed T cell ratio in suppression assays. In addition, we examined the reported paradoxical proinflammatory effects of IFN-γ and confirmed in this system that late IFN-γ exposure does not inhibit DC maturation marker expression. Early IFN-γ exposure is critical in promoting the generation of regulatory DC. Early IFN-γ modulated DC generated in 48h are maturation arrested and promote the generation of antigen-specific regulatory T cells, which may be clinically applicable as a novel cellular therapy for allograft rejection.

    Original languageEnglish
    Pages (from-to)447-458
    Number of pages12
    JournalClinical and Experimental Immunology
    Volume167
    Issue number3
    DOIs
    Publication statusPublished - Mar 2012

    Keywords

    • Dendritic cells
    • Interferon-γ
    • NF-κB
    • STAT-6
    • Transplantation

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