Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance
Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance
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DOI：
10.1681/asn.2014050480
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发表时间：
2015-08-01
影响因子：
13.6
通讯作者：
Brouard, Sophie
中科院分区：
文献类型：
--
作者：
Braza, Faouzi;Dugast, Emilie;Brouard, Sophie
Foxp3(+) 调节性 T 细胞 (Treg) 在操作耐受性中的作用仍然难以捉摸，因为初步结果显示该亚群在耐受患者中的频率增加，但与免疫抑制受体相比没有功能差异。此外，最近对调节性 B 细胞的研究强烈表明，Treg 可能在肾移植耐受性中不起核心作用。然而，最近对 Foxp3 去甲基化在 Treg 功能中的关键作用以及识别不同 Foxp3 T 细胞亚群的可能性的研究促使我们更全面地表征手术耐受患者中的 Tregs。因此，我们研究了循环CD4+T细胞中Foxp3 Treg特异性去甲基化区域（TSDR）的去甲基化水平，并分析了耐受患者、健康志愿者、免疫抑制下移植功能稳定的患者和长期排斥受体的Treg亚群频率。我们仅在耐受患者中观察到具有去甲基化 Foxp3 的 CD4(+) T 细胞比例较高，并且 CD4(+) CD45RA(-) Foxp3(hi) 记忆 Tregs 特异性扩增。耐受受体的记忆Tregs表现出Foxp3 TSDR去甲基化增加，表达更高水平的CD39和糖皮质激素诱导的TNF相关受体，并且比移植功能稳定的患者的记忆Tregs具有更大的抑制特性。总而言之，我们的数据表明，操作耐受的患者会动员一系列潜在的抑制细胞，不仅包括调节性 B 细胞，还包括 Tregs。我们的结果还表明，耐受性患者具有强效的 CD4(+)CD45RA(-) Foxp3(hi) 记忆性 Tregs，具有特定的 Foxp3 TSDR 去甲基化模式，这可能有助于维持移植物耐受性。
The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.