Long-Term Allograft Tolerance Is Characterized by the Accumulation of B Cells Exhibiting an Inhibited Profile

Authors

  • L. Le Texier,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • P. Thebault,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • A. Lavault,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • C. Usal,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • E. Merieau,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • T. Quillard,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • B. Charreau,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • J. P. Soulillou,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • M. C. Cuturi,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • S. Brouard,

    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
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  • E. Chiffoleau

    Corresponding author
    1. INSERM U643, Nantes, F44000 France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, ITUN, Nantes, F44000 France; Université de Nantes, Faculté de Médecine, Nantes, F44000 France
      Corresponding author: Elise Chiffoleau, Elise.Chiffoleau@univ-nantes.fr
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Corresponding author: Elise Chiffoleau, Elise.Chiffoleau@univ-nantes.fr

Abstract

Numerous reports have highlighted the central role of regulatory T cells in long-term allograft tolerance, but few studies have investigated the B-cell aspect. We analyzed the B-cell response in a rat model of long-term cardiac allograft tolerance induced by a short-term immunosuppression. We observed that tolerated allografts are infiltrated by numerous B cells organized in germinal centers that are strongly regulated in their IgG alloantibody response. Moreover, alloantibodies from tolerant recipients exhibit a deviation toward a Th2 isotype and do not activate in vitro donor-type endothelial cells in a pro-inflammatory way but maintained expression of cytoprotective molecules. Interestingly, this inhibition of the B-cell response is characterized by the progressive accumulation in the graft and in the blood of B cells blocked at the IgM to IgG switch recombination process and overexpressing BANK-1 and the inhibitory receptor Fcgr2b. Importantly, B cells from tolerant recipients are able to transfer allograft tolerance. Taken together, these results demonstrate a strong regulation of the alloantibody response in tolerant recipients and the accumulation of B cells exhibiting an inhibited and regulatory profile. These mechanisms of regulation of the B-cell response could be instrumental to develop new strategies to promote tolerance.

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