IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells

Authors

  • Marcelo Hill,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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    • First two authors contributed equally to this work.

  • Séverine Tanguy-Royer,

    1. INSERM, U 601 Nantes, France
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    • First two authors contributed equally to this work.

  • Pierre Royer,

    1. INSERM, U 601 Nantes, France
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  • Christine Chauveau,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Kashif Asghar,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Laurent Tesson,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Frédéric Lavainne,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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    • First two authors contributed equally to this work.

  • Séverine Rémy,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Régis Brion,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • François-Xavier Hubert,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Michèle Heslan,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Marie Rimbert,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Laureline Berthelot,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • John R. Moffett,

    1. Department of Anatomy, Uniformed Services University of the Health Sciences, Bethesda, USA
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  • Régis Josien,

    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
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  • Marc Grégoire,

    1. INSERM, U 601 Nantes, France
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    • Last two authors contributed equally to this work.

  • Ignacio Anegon M.D.

    Corresponding author
    1. INSERM, U 643, Nantes, France
    2. CHU Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
    3. Université de Nantes, Faculté de Médecine, Nantes, France
    • MD, INSERM, U 643, ITERT, 30 Bd. Jean Monnet, 44093 Nantes, Cedex 1, France, Fax: +33-2-40-08-74-11
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    • Last two authors contributed equally to this work.


Abstract

We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-α + poly(I:C)-induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPS-induced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPS-treated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-κB activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4+CD25high regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4+CD25high regulatory T cells.

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