CD4+ T Cells from IPEX Patients Convert into Functional and Stable Regulatory T Cells by FOXP3 Gene Transfer
CD4+ T Cells from IPEX Patients Convert into Functional and Stable Regulatory T Cells by FOXP3 Gene Transfer
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DOI：
10.1126/scitranslmed.3007320
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发表时间：
2013-12-11
影响因子：
17.1
通讯作者：
Bacchetta, Rosa
中科院分区：
文献类型：
--
作者：
Passerini, Laura;Mel, Eva Rossi;Bacchetta, Rosa
在人类中，叉头框 P3 (FOXP3) 编码基因的突变可导致危及生命的系统性多发性自身免疫性疾病，称为免疫失调、多内分泌病、肠病、X 连锁 (IPEX) 综合征。叉头盒 P3 是 CD4(+)CD25(+) 调节性 T (T-reg) 细胞功能极其重要的转录因子。 FOXP3 突变的 T reg 细胞的先天功能障碍和不稳定性导致严重的自身免疫。造血干细胞移植是目前受影响患者唯一的治疗选择。我们在此表明，当慢病毒介导的FOXP3基因转移后CD4(+) T细胞转化为T-reg细胞时，所得的CD4(FOXP3) T细胞群体表现出稳定的表型和抑制功能，特别是当幼稚T细胞转化时。我们进一步证明，CD4(FOXP3) T 细胞不仅在体外，而且在异种移植物抗宿主病模型中的体内炎症条件下均稳定。因此，我们应用这种 FOXP3 基因转移策略来开发基于 T-reg 细胞的治疗方法，以恢复 IPEX 综合征的耐受性。 IPEX 衍生的 CD4(FOXP3) T 细胞在细胞标记、无反应表型、细胞因子产生和抑制功能方面与健康供体的 T-reg 细胞相似。这些发现为通过基因工程 T-reg 细胞的过继细胞疗法治疗 IPEX 患者铺平了道路，并且对于未来在不同来源的自身免疫性疾病患者中的潜在应用具有重要意义。
In humans, mutations in the gene encoding for forkhead box P3 (FOXP3), a critically important transcription factor for CD4(+)CD25(+) regulatory T (T-reg) cell function, lead to a life-threatening systemic poly-autoimmune disease, known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Severe autoimmunity results from the inborn dysfunction and instability of FOXP3-mutated T-reg cells. Hematopoietic stem cell transplantation is the only current curative option for affected patients. We show here that when CD4(+) T cells are converted into T-reg cells after lentivirus-mediated FOXP3 gene transfer, the resulting CD4(FOXP3) T cell population displays stable phenotype and suppressive function, especially when naive T cells are converted. We further demonstrate that CD4(FOXP3) T cells are stable in inflammatory conditions not only in vitro but also in vivo in a model of xenogeneic graft-versus-host disease. We therefore applied this FOXP3 gene transfer strategy for the development of a T-reg cell-based therapeutic approach to restore tolerance in IPEX syndrome. IPEX-derived CD4(FOXP3) T cells mirrored T-reg cells from healthy donors in terms of cellular markers, anergic phenotype, cytokine production, and suppressive function. These findings pave the way for the treatment of IPEX patients by adoptive cell therapy with genetically engineered T-reg cells and are seminal for future potential application in patients with autoimmune disorders of different origin.