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Génération et fonctions des macrophages immunorégulateurs

Etienne Foucher 1
1 CRCINA-ÉQUIPE 7 - Innate Immunity and Immunotherapy
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Abstract : According to the soluble factors in the environment (cytokines), monocytes differentiate into macrophages (Mϕ) or dendritic cells. This project demonstrates that IL-34, a second ligand of the M-CSF receptor (c-fms or CD115), induces the differentiation of human monocytes into CD14high CD163 high Mφ (IL-34-Mφ), phenotypically and functionally similar to M-CSF-Mφ and to tumorassociated macrophages (TAM) isolated from the ovarian cancer. They exhibit potent immunosuppressive properties and decrease the proliferation of stimulated Tcells. As Mφ orchestrate the immune response, I have evaluated the capacity of M-CSF-Mφ, IL-34-Mφ and TAM to polarize human memory CD4+ T cells. Unexpectedly, results showed that they switch non- Th17 memory CD4+ T cells into conventional CCR4+ CCR6+ CD161+ Th17 cells, expressing or not IFNγ. This process is mediated by the constitutive expression of membrane IL-1α on these Mϕ subsets. In an attempt to identify strategies to prevent an accumulation of immunomodulatory Mϕ in cancer, I have shown that (i) IFNγ and GM-CSF prevent M-CSFandIL-34-induced monocyte differentiation into immunosuppressive Mφ and (ii) that IFNγ switchesestablished M-CSF-Mφ and IL-34-Mφ into immunostimulatory Mφ. In conclusion, this study demonstrates that human MCSF- Mφ, IL-34-Mφ and TAM initially considered as antiinflammatorycells, induce in vitro Th17 cell generation via a constitutive expression of membrane IL-1α. This process may contribute to maintain locally a restrained and smoldering inflammation required for angiogenesis and metastasis in tumors.
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Etienne Foucher. Génération et fonctions des macrophages immunorégulateurs. Médecine humaine et pathologie. Université d'Angers, 2015. Français. ⟨NNT : 2015ANGE0056⟩. ⟨tel-02078274⟩

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