Transplantation

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Mhc-ii Donor Peptides Activates human cd8+cd45rclow Tregs Secreting Ifng, il-10, il-34 and Tgfb to Inhibit Human Transplant Rejection

Thursday, June 15
5:45 PM - 7:00 PM

Introduction: We previously reported the suppressive properties of rat CD8+CD45RClowTreg cells. To date, human counterparts have never been studied for their relevance as a cell-based therapy.


Materials and Methods: Cytokine secretion assay kits were used to sort IFNg/IL10 secreting Tregs from healthy volunteers PBMCs by FACSAria. Tregs were expanded for 14 days with anti-CD3/CD28 mAbs, allogeneic APCs or syngeneic APCs and peptide and analyzed for TCR repertoire. Suppressive function was assessed in vitro on syngeneic CD4+CD25-T cells stimulated by alloAPCs, and in vivo into NSG mice infused with PBMCs and grafted or not with allogeneic human skin for allograft survival and xenogeneic GVHD studies.


Results: We demonstrated that human CD8+CD45RClowT cells contain natural regulatory cells expressing Foxp3 and GITR and secreting IFNg, IL-10, TGFbeta and IL-34. CD45RClowCD8+ Tregs inhibited allogeneic T cell proliferation, more efficiently than classical CD4+Tregs. Cytokines and a preferential contact with pDCs were required for CD8+CD45RClow Tregs suppressive activity, but no cytotoxicity. We developed a protocol to expand CD8+Tregs using IL-2, IL-15 and donor antigens and obtained up to 2000 fold expansion. Expanded Tregs displayed a biased TCR with restricted and private alpha and beta chain repertoire. We showed that CD8+ Tregs recognized a dominant 16aa peptide derived from donor MHC class II molecules, expanding and activating their suppressive function. Expanded CD8+CD45RClowTregs were highly suppressive in vitro and in vivo significantly delayed GVHD development and allogeneic skin graft rejection in humanized mice.


Conclusions:We identified and characterized a new natural regulatory T cell population as a promising candidate for cell therapy.


 

Séverine Bézie

INSERM UMR 1064-CRTI

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    Laetitia Boucault

    INSERM UMR1064 - CRTI

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      Dimitri Meistermann

      INSERM UMR1064 CRTI

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        Véronique Daguin

        INSERM UMR 1064-CRTI and Nantes University

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          Elodie Autrusseau

          Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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            Frédérique Bellier Waast

            CHU Nantes

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              Franck Duteille

              CHU Nantes

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                Ignacio Anegon

                Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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                  Carole Guillonneau

                  CNRS
                  Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France

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                    Mhc-ii Donor Peptides Activates human cd8+cd45rclow Tregs Secreting Ifng, il-10, il-34 and Tgfb to Inhibit Human Transplant Rejection



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