美国哈佛医学院Christophe Benoist、Diane Mathis等研究人员合作揭示FOXP3缺陷对CD4⁺T的影响。2021年4月8日，《自然—免疫学》杂志在线发表这一论文。

研究人员表示，小鼠和患有免疫失调的多发性内分泌病性肠病X连锁（IPEX）综合征患者中的FOXP3缺失，会通过改变调节性T（T_reg）细胞而导致致命的自身免疫。

通过单细胞流式细胞仪和RNA测序对IPEX综合征和Foxp3缺陷小鼠的CD4⁺T细胞分析，研究人员发现异质性T_reg样细胞，有些与正常T_reg细胞非常相似，而另一些则较远。传统的T细胞没有显示出广泛的激活或辅助性T细胞偏向性，但是单态性疾病特征影响了所有CD4⁺T细胞。该信号被证明是细胞外源性的，因为它已在混合型骨髓嵌合小鼠和IPEX综合征患者的杂合子母亲中消失。正常的T_reg细胞发挥显性抑制作用，抑制疾病信号，并在突变的T_reg样细胞中揭示出一小群由FOXP3调节的基因，包括关键的稳态调节因子。

研究人员提出了一个两步发病机制模型：核心FOXP3依赖基因的下调使T_reg细胞不稳定，使得在所有T细胞上都具有的系统性介导因子去抑制，从而进一步加剧T_reg细胞功能障碍。因此，白介素2治疗改善了T_reg样区室和存活。 

附：英文原文

Title: Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4 + T cell perturbations

Author: David Zemmour, Louis-Marie Charbonnier, Juliette Leon, Emmanuelle Six, Sevgi Keles, Marianne Delville, Mehdi Benamar, Safa Baris, Julien Zuber, Karin Chen, Benedicte Neven, Maria I. Garcia-Lloret, Frank M. Ruemmele, Carlo Brugnara, Nadine Cerf-Bensussan, Frederic Rieux-Laucat, Marina Cavazzana, Isabelle Andr, Talal A. Chatila, Diane Mathis, Christophe Benoist

Issue&Volume: 2021-04-08

Abstract: FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival. FOXP3 deficiency leads to dramatic loss of immune homeostasis. This multicenter collaborative group finds that loss of FOXP3 function only disrupts a few core genes, but this unmasks a degree of systemic inflammation, and it is this environment that then strongly perturbs Treg cells.

DOI: 10.1038/s41590-021-00910-8

Source: https://www.nature.com/articles/s41590-021-00910-8