Alvarez Salazar Evelyn Katy, Cortés-Hernández Arimelek, Alemán-Muench Germán Rodrigo, Alberú Josefina, Rodríguez-Aguilera Jesús R, Recillas-Targa Félix, Chagoya de Sánchez Victoria, Cuevas Eric, Mancilla-Urrea Eduardo, Pérez García María, Mondragón-Ramírez Guillermo, Vilatobá Mario, Bostock Ian, Hernández-Méndez Erick, De Rungs David, García-Zepeda Eduardo A, Soldevila Gloria
Departmento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México , Ciudad de México , Mexico.
Departmento de Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Ciudad de México , Mexico.
Front Immunol. 2017 Mar 3;8:219. doi: 10.3389/fimmu.2017.00219. eCollection 2017.
Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4CD25CD127FOXP3 T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA "naïve" Tregs, while the expression of Helios, a marker used to identify stable FOXP3 thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.
调节性T细胞（Tregs）被认为是预防移植患者同种异体移植排斥反应的关键因素。贝拉西普（BLT）是钙调神经磷酸酶抑制剂的有效替代品，似乎能维持移植物的存活和功能；然而，这种药物对移植患者Tregs稳态的影响仍存在争议。在此，我们分析了长期接受BLT或环孢素A治疗的肾移植患者循环Tregs中FOXP3的Treg特异性去甲基化区域（TSDR）的表型、功能和表观遗传状态。我们发现，与健康个体（对照组）相比，所有患者中CD4CD25CD127FOXP3 T细胞的比例均显著降低。有趣的是，只有接受BLT治疗的患者表现出CD45RA“幼稚”Tregs的富集，而用于识别稳定FOXP3胸腺Tregs的标志物Helios的表达未受影响。功能分析表明，与对照组的Tregs相比，移植患者的Tregs抑制能力显著降低，这与FOXP3和CD25水平降低有关。对FOXP3基因甲基化状态的分析表明，BLT治疗导致TSDR内CpG岛甲基化，这可能与Treg抑制功能受损有关。我们的数据表明，循环Tregs分析不能用作评估长期肾移植患者对同种异体移植物耐受性的标志物。试验注册号IM103008。
