Regulatory T cells were recently proposed as the central actor in operational tolerance after renal transplantation. Tolerant patients harbor increased FoxP3hi memory Treg frequency and increased demethylation in the Foxp3 Treg-specific demethylated region when compared to stable kidney recipients and exhibit greater memory Treg suppressive capacities and higher expression of the ectonucleotidase CD39. However, in this particular and unique situation the mechanisms of action of Tregs were not identified. Thus, we analyzed the ability of memory Tregs to degrade extracellular ATP in tolerant patients, healthy volunteers, and patients with stable graft function under immunosuppression and determined the role of immunosuppressive drugs on this process. The conserved proportion of memory Tregs leads to the establishment of a pro-tolerogenic balance in operationally tolerant patients. Memory Tregs in tolerant patients display normal capacity to degrade extracellular ATP/ADP. In contrast, memory Tregs from patients with stable graft function do not have this ability. Finally, in vitro, immunosuppressive drugs may favor the lower proportion of memory Tregs in stable patients, but they have no effect on CD39-dependent ATP degradation and do not explain memory Treg lack of extracellular ATP/ADP degradation ability. Thus, intrinsic active regulatory mechanisms may act long after immunosuppressive drug arrest in operationally tolerant patients and may contribute to kidney allograft tolerance via the maintenance of CD39 Treg function.
Kidney international. 2018 Feb 15 [Epub ahead of print]
Maxim Durand, Florian Dubois, Cécile Dejou, Eugénie Durand, Richard Danger, Mélanie Chesneau, Carole Brosseau, Pierrick Guerif, Jean-Paul Soulillou, Nicolas Degauque, Jean-François Eliaou, Magali Giral, Nathalie Bonnefoy, Sophie Brouard
Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France., OREGA Biotech, Ecully, France; IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U1194; Université Montpellier; Institut Régional du Cancer de Montpellier, Montpellier, France., Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France., Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Centre d'Investigation Clinique (CIC) Biothérapie, CHU Nantes, Nantes, France., IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U1194; Université Montpellier; Institut Régional du Cancer de Montpellier, Montpellier, France; Département d'Immunologie, Centre Hospitalier Universitaire de Montpellier et Faculté de Médecine, Université de Montpellier, Hôpital Saint-Eloi, Montpellier, France., IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U1194; Université Montpellier; Institut Régional du Cancer de Montpellier, Montpellier, France., Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France; Centre d'Investigation Clinique (CIC) Biothérapie, CHU Nantes, Nantes, France. Electronic address: .