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.
Kidney Int. 2018 May;93(5):1154-1164. doi: 10.1016/j.kint.2017.12.004. Epub 2018 Feb 15.
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.
调节性 T 细胞最近被提出作为肾移植后获得性免疫耐受的核心作用细胞。与稳定的肾移植受者相比，耐受患者的 FoxP3hi 记忆 Treg 频率增加，Foxp3 Treg 特异性去甲基化区域的去甲基化增加，并且表现出更强的记忆 Treg 抑制能力和更高的外核苷酸酶 CD39 表达。然而，在这种特殊而独特的情况下，Tregs 的作用机制尚未确定。因此，我们分析了记忆 Tregs 在耐受患者、健康志愿者和接受免疫抑制治疗的稳定移植物功能患者中降解细胞外 ATP 的能力，并确定了免疫抑制药物对该过程的作用。记忆 Tregs 的保守比例导致在获得性免疫耐受患者中建立了促耐受的平衡。耐受患者的记忆 Tregs 具有正常降解细胞外 ATP/ADP 的能力。相比之下，稳定移植物功能患者的记忆 Tregs 则没有这种能力。最后，在体外，免疫抑制药物可能有利于稳定患者中记忆 Tregs 的比例降低，但它们对 CD39 依赖的 ATP 降解没有影响，也不能解释记忆 Treg 缺乏降解细胞外 ATP/ADP 的能力。因此，内在的主动调节机制可能在获得性免疫耐受患者停止免疫抑制药物治疗后很长时间内发挥作用，并通过维持 CD39 Treg 功能来促进肾移植耐受。
