title: Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance.
abstract: In transplantation tolerance, numerous regulatory populations have the capacity to inhibit allograft rejection; however, their compensatory capacities have never been clearly evidenced. We have previously demonstrated that the tolerogenic effect mediated by CD8(+)CD45RC(low) regulatory T cells (Tregs) in a model of organ transplantation with CD40Ig could be abrogated by permanent depletion of CD8(+) cells that resulted in allograft rejection in half of the recipients. This result demonstrated that CD8(+) Tregs were essential, but also that half of the recipients still survived indefinitely. We also demonstrated that no other regulatory populations, besides CD8(+) Tregs, could induce and maintain allograft tolerance in CD40Ig-treated tolerant animals. In the current study, we analyzed the mechanisms that arose following CD8(+) Treg depletion and allowed establishment of networks of new regulatory cells to maintain allograft survival. We identified regulatory B cells (Bregs) and regulatory myeloid cells (RegMCs) as being responsible of the maintenance of the long-term allograft survival. We demonstrated that both regulatory cell subsets efficiently inhibited antidonor immune responses in adoptively transferred recipients. Although Bregs were induced, they were not essential for the maintenance of the graft as demonstrated in IgM-deficient recipients. In addition, we showed that RegMCs were the most suppressive and acted alone, whereas Bregs activity was associated with increased suppressive activity of other subsets in adoptively transferred recipients. Altogether, to our knowledge, we demonstrated in this study for the first time the emergence of both Bregs and RegMCs following Tregs depletion and highlighted the importance of regulatory cell networks and their synergistic potential in transplantation.
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bézie
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Picarda
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France.
authors.forename: Jason
authors.initials: J
authors.lastname: Ossart
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Martinet
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.affiliation: INSERM UMR1064-Centre de Recherche en Transplantation et Immunologie-Institut de Transplantation et de Recherche en Urologie et Néphrologie, 44093 Nantes, France; andCentre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, 44093 Nantes, France carole.guillonneau@univ-nantes.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Guillonneau
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D056747:Immunomodulation; D022423:Myeloid Cells / Q000276:immunology* / Q000637:transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D023001:Transplantation Tolerance