San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
J Allergy Clin Immunol. 2018 Dec;142(6):1909-1921.e9. doi: 10.1016/j.jaci.2018.03.015. Epub 2018 Apr 27.
Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed.
We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology.
We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice).
Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a T2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels.
These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome.
叉头框 P3（FOXP3）是调节性 T（Treg）细胞功能的关键转录因子。FOXP3 基因突变导致免疫失调、多内分泌腺病、肠病、X 连锁（IPEX）综合征，这是一种致命的自身免疫综合征。FOXP3 也被提议在效应 T（Teff）细胞中发挥作用，但迄今为止，这一作用尚未得到证实。
我们旨在评估降低 FOXP3 表达对人 Treg 和 Teff 细胞发育的影响，并将其与 IPEX 综合征免疫病理学相关联。
我们开发了一种人源化小鼠（huMice）模型，其中人造血系统被稳定敲低或敲除 FOXP3 基因（敲低[KD]/敲除[KO]huMice）。
由于 FOXP3-KD/KO 不是 100%有效，造血干细胞祖细胞中残留的 FOXP3 表达足以产生 FOXP3 表达正常的 Treg 细胞。然而，Teff 细胞区室出现了许多缺陷。与对照小鼠相比，FOXP3-KD/KO huMice 显示出改变的胸腺细胞分化，KD/KO 胸腺细胞表现出明显降低的 T 细胞受体（TCR）信号强度和增加的 TCR repertoire 多样性。外周 KD/KO Teff 细胞扩增，并显示出稳态增殖的迹象，例如 TCR repertoire 明显收缩，幼稚细胞区室严重减少，端粒重复结合因子 2 表达减少，并且向 T2 表型倾斜，类似于衰老的免疫系统。与 FOXP3-KD/KO huMice 的结果一致，对 IPEX 综合征患者的分析提供了在胸腺和外周水平 Teff 细胞区室缺陷的证据。
这些发现支持人类 FOXP3 在控制胸腺细胞成熟和外周 Teff 细胞扩增中的内在作用，并揭示了一种以前未描述的通过 IPEX 综合征患者改变的 Teff 细胞区室的致病机制。
