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Studying the mode of action and homeostasis of regulatory T cells

from basic science:
  • immune tolerance
  • lymphocytes
to the translational research:
  • gene therapy
  • transplantation
Jean Davoust
Regulatory T cell biology and biotherapy applications

Jean Davoust is CNRS Research Director and Immunologist, gained a Ph.D. in membrane biophysics, was trained in cell biology and physical instrumentation at EMBL (Heidelberg, Germany), pioneered confocal imaging in France (CIML, Marseilles), deciphered MHC class II trafficking and antigen presentation in dendritic cells and joined the Baylor Institute for Immunology Research (BIIR, Dallas TX) to settled new immunization strategies for anti-tumor immunotherapy. With David Gross we developed a novel strategy to induce antigen-specific tolerance with regulatory T cells tailored for gene therapy applications achieved with recombinant AAV vectors. J. Davoust has a dual expertise in immunology and confocal imaging, and devoted his career to unraveling MHC presentation processes and T cell mediated regulation of adaptive immune responses.

J. Davoust authored 98 publications with over 13000 citations, H index 49.

Focus

Our laboratory studies the recruitment of regulatory T lymphocytes with applications in gene and cell therapies. We wish manipulate antigen presentation pathways to induce immune tolerance to novel medicine gene therapy interventions.

Introduction

Regulatory T (Treg) cells are particularly important to maintain self-tolerance, shield spontaneous activation of autoreactive T cells in inflamed tissues and are mandatory to maintain immune homeostasis at environmental interfaces. Treg cells are also instrumental to promote immune tolerance to grafts and to medicinal products or therapeutic transgenes delivered with viral vectors.

Our laboratory addresses the mechanisms governing homeostasis and function of CD4+ Foxp3+ regulatory T lymphocytes with defined applications in the field of gene and cell therapies. Regarding the mode of action and the suppression-efficiency of antigen-specific Treg cells expressing a defined T cell receptor, we established that:

  • Treg cells have to be present before gene transfer to inhibit all cellular and humoral responses to the transgene.
  • Treg cells can be expanded by antigen-recognition events in the absence of inflammatory signals in the periphery.
  • de novo Treg cells generation occurs in the periphery in parallel with tissue engraftment, all of which are severely hampered in elderly.

Major areas of interest of our team include:

  • Deciphering quantitative traits of Treg cells activation in lymphopenic environments.
  • Assessing the importance of the direct and cross-presentation pathways of CD8+ T cell epitopes on the outcome of CD8+ T cell responses to transgenes expressed in peripheral tissues.
  • Deciphering the interactions of Treg cells with innate cells such as dendritic cells and mastocyte in cutaneous anaphylaxis and skin transplantation models.

Research objectives

Treg cells are educated in the thymus by unresolved antigen-specific interactions as a diversion of the CD4+ T cell lineage, whereas a minor proportion of Treg cells emerge in the periphery by conversion of conventional CD4+ T cells. The relationship between antigen-specific Treg cells education in the thymus and their functional activation in the periphery is unresolved. Moreover, the recruitment of antigen-specific Treg cells leading to induction of dominant tolerance to foreign antigens is difficult to reach and antigenic determinants recognized by Treg cells have not been characterized at the molecular level.

To approach these questions we explore:

  • How antigenic determinants of delivered in vivo with non-replicative, non-integrative recombinant Adeno-associated vectors (rAAV) are processed and presented to T cells and how direct and indirect antigen-presentation pathways of tissue associated antigens gear CD8+ T cell responses towards immunity or tolerance.
  • Whether antigen-specific Treg cells are recruited locally after tissue transplantation or rAAV-mediated gene transfer in target tissues.
  • Whether Treg cells establish particular interactions with dendritic cells during the initiation and/or the tolerization of immune responses.

Our long-term perspective is to manipulate antigen presentation pathways and mobilize antigen-specific Treg cells in order to induce tolerance to foreign antigens in regenerative medicine applications. Moreover, we expect that these modalities will be important to restore tissue-specific tolerance in autoimmunity patients.

5 main publications

  • Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia.
    Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, Da Costa de Jesus C, Lhermitte L, Tesio M, Dussiot M, Cosset FL, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross DA, Hermine O, Macintyre E, Ghysdael J, Asnafi V.
    Cancer Discov. 2016 Sep;6(9):972-85. doi: 10.1158/2159-8290.CD-15-0675.
  • Intrinsic Transgene Immunogenicity Gears CD8+ T-cell Priming After rAAV-Mediated Muscle Gene Transfer.
    Carpentier M, Lorain S, Chappert P, Lalfer M, Hardet R, Urbain D, Peccate C, Adriouch S, Garcia L, Davoust J, Gross DA.
    Mol Ther. 2015 Apr;23(4):697-706.
  • Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis.
    Dahdah A, Gautier G, Attout T, Fiore F, Lebourdais E, Msallam R, Daëron M, Monteiro RC, Benhamou M, Charles N, Davoust J, Blank U, Malissen B, Launay P.
    J Clin Invest. 2014 Oct;124(10):4577-89.
  • Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation.
    Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J, Maddur MS, Park Y, Jones DP, Chappert P, Davoust J, Weiss DS, Virgin HW, Ron D, Pulendran B.
    Science. 2014 Jan 17;343(6168):313-7.
  • Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T-cell intrinsic manner.
    Carpentier M, Chappert P, Kuhn C, Lalfer M, Flament H, Burlen-Defranoux O, Lantz O, Bandeira A, Malissen B, Davoust J, Gross DA.
    Eur J Immunol. 2013 Oct;43(10):2598-604.
Last 30 publications

2016

  • Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, Da Costa de Jesus C, Lhermitte L, Tesio M, Dussiot M, Cosset FL, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross DA, Hermine O, Macintyre E, Ghysdael J, Asnafi V. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia. Cancer Discov. 2016 Jun 28. [Epub ahead of print] PMID: 27354269.
  • Goudin N, Chappert P, Mégret J, Gross DA, Rocha B, Azogui O. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells. PLoS One. 2016 Jun 24;11(6):e0157822. doi: 10.1371/journal.pone.0157822.
  • 2015

  • Carpentier M, Lorain S, Chappert P, Lalfer M, Hardet R, Urbain D, Peccate C, Adriouch S, Garcia L, Davoust J, Gross DA. Intrinsic transgene immunogenicity gears CD8(+) T-cell priming after rAAV-mediated muscle gene transfer. Mol Ther. 2015 Apr;23(4):697-706.
  • 2014

  • Dahdah A, Gautier G, Attout T, Fiore F, Lebourdais E, Msallam R, Daëron M, Monteiro RC, Benhamou M, Charles N, Davoust J, Blank U, Malissen B, Launay P. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis. J Clin Invest. 2014 Oct;124(10):4577-89.
  • Ravindran R, Khan N, Nakaya HI, Li S, Loebbermann J, Maddur MS, Park Y, Jones DP, Chappert P, Davoust J, Weiss DS, Virgin HW, Ron D, Pulendran B. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science. 2014 Jan 17;343(6168):313-7.
  • 2013

  • Carpentier M, Chappert P, Kuhn C, Lalfer M, Flament H, Burlen-Defranoux O, Lantz O, Bandeira A, Malissen B, Davoust J, Gross DA. Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T-cell intrinsic manner. Eur J Immunol. 2013 Oct;43(10):2598-604.
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    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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