BACKGROUND Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

中文翻译：

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雷帕霉素治疗可以恢复IPEX患者的调节性T细胞功能。

背景技术免疫失调，多内分泌病，肠病，X连锁（IPEX）综合征是一种致命疾病，是由对胸腺来源的调节性T（Treg）细胞（即FOXP3）的功能至关重要的转录因子突变引起的，导致受损Treg功能和自身免疫。目前，造血干细胞移植是IPEX综合征患者的首选治疗方法。如果无法获得，则在长期随访中已采用多种免疫抑制方案，且无病生存期较差。雷帕霉素已显示出抑制外周血T细胞，同时保留表达野生型FOXP3的Treg细胞，从而证明在免疫失调的临床环境中是有益的。但是，尚不清楚IPEX综合征患者对Treg细胞有选择性的免疫抑制机制。目的我们试图确定雷帕霉素治疗对6名具有不同FOXP3突变的IPEX综合征患者的临床益处的细胞和分子基础。方法采用流式细胞术和体外抑制试验检测雷帕霉素治疗的IPEX综合征患者FOXP3突变的Treg细胞的表型和功能，并采用液滴数字PCR检测雷帕霉素调节的Treg细胞的基因表达谱。结果患者的临床和组织学改善与Treg功能部分恢复有关，而与FOXP3表达或Treg频率无关。TNF-α超家族成员18（TNFRSF18，糖皮质激素诱导的TNF-受体相关）和EBV-诱导的3（EBI3，IL-35亚基）的表达 与未经治疗的健康受试者的Treg细胞相比，治疗期间Treg细胞增加。此外，对糖皮质激素诱导的TNF受体相关和Ebi3的抑制作用在体内被雷帕霉素调节的Treg细胞体外抑制作用部分恢复。结论雷帕霉素能够通过不依赖FOXP3的机制影响Treg抑制功能，从而维持雷帕霉素治疗下IPEX综合征患者的临床改善。