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Inhibition of PI3K/C/EBPβ axis in tolerogenic bone marrow-derived dendritic cells of NOD mice promotes Th17 differentiation and diabetes development

  • Author Footnotes
    # These authors contributed equally to this work.
    Chantal Guindi
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Author Footnotes
    # These authors contributed equally to this work.
    Farhan Ullah Khan
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
    Search for articles by this author
  • Alexandre Cloutier
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Puregmaa Khongorzul
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Ahmed Aziz Raki
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Simon Gaudreau
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Patrick P. McDonald
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Denis Gris
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
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  • Abdelaziz Amrani
    Correspondence
    Reprint requests: Abdelaziz Amrani, Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada.
    Affiliations
    Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
Published:November 14, 2022DOI:https://doi.org/10.1016/j.trsl.2022.11.005

      Abstract

      Dendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic dendritic cells play a crucial role in inducing and maintaining immune tolerance in autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse model. We previously reported that bone marrow-derived DCs (BM.DCs) from NOD mice, generated with a low dose of GM-CSF (GM/DCs), induce Treg differentiation and are able to protect NOD mice from diabetes. We had also found that the p38 MAPK/C/EBPβ axis is involved in regulating the phenotype, as well as the production of IL-10 and IL-12p70, by tolerogenic GM/DCs. Here, we report that the inhibition of the PI3K signaling switched the cytokine profile of GM/DCs toward Th17-promoting cytokines without affecting their phenotype. PI3K inhibition abrogated the production of IL-10 by GM/DCs, whereas it enhanced their production of IL-23 and TGFβ. Inhibition of PI3K signaling in tolerogenic GM/DCs also induced naive CD4+ T cells differentiation toward Th17 cells. Mechanistically, PI3K inhibition increased the DNA-binding activity of C/EBPβ through a GSK3-dependent pathway, which is important to maintain the semimature phenotype of tolerogenic GM/DCs. Furthermore, analysis of C/EBPβ−/− GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological relevance, the level of protection from diabetes following transfusion of GM/DCs into young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.
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