Medical Department, Division of Rheumatology and Clinical Immunology, Charité-University Medicine, Berlin, Germany.
Ann Rheum Dis. 2013 Sep 1;72(9):1549-58. doi: 10.1136/annrheumdis-2012-202216. Epub 2012 Dec 21.
Recent data debate the suitability of Helios, an Ikaros family member, as a marker for thymic-derived regulatory T cells (Treg). Nevertheless, Foxp3(+) Helios(+) Treg may be of particular relevance in mediating immune tolerance in chronic autoimmunity, such as systemic lupus erythematosus (SLE), as they possess enhanced suppressive function, compared to Foxp3(+) Helios(-) Treg.
Multicolour flow cytometry was performed to analyse Foxp3 and Helios expression in peripheral blood CD4 T cells from SLE patients, compared to healthy controls (HC) and systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. Cytokine production, chemokine receptor expression for CXCR3 and CCR4, basal signal transducer and activator of transcription 5 (STAT5)a phosphorylation levels and T-cell receptor (TCR) Vβ repertoire were analysed by flow cytometry, and the methylation status of the Foxp3 locus (Treg-specific demethylated region, TSDR) by real-time PCR.
Frequencies of Foxp3(+) Helios(+) Treg, unlike Foxp3(+) Helios(-) T cells, were significantly increased in SLE patients and positively correlated with disease activity, whereas they were unaltered in SSc and RA patients. Compared to HC, Foxp3(+) Helios(+) Treg in SLE predominantly displayed a CD45RA(-)/CD31(-)/FoxP3(low) memory phenotype with increased Ki-67 expression, enhanced basal pSTAT5a levels and a restricted TCR repertoire. Nonetheless, similar to HC, Foxp3(+) Helios(+) Treg in SLE lacked effector cytokine production, possessed a highly demethylated TSDR and expressed comparable levels of CXCR3 and CCR4.
Our data suggest that Helios-expressing Foxp3(+) Treg with functional suppressive capacity and migratory potential into inflamed tissues are expanded in active SLE, presumably through γ-chain signalling cytokines and TCR stimulation, to compensate for autoreactive effector responses.
最近的数据对 Helios（Ikaros 家族的一员）作为胸腺来源的调节性 T 细胞（Treg）标志物的适用性提出了质疑。然而，与系统性红斑狼疮（SLE）等慢性自身免疫性疾病相关的 Foxp3(+)Helios(+)Treg 可能具有特别重要的意义，因为它们与 Foxp3(+)Helios(-)Treg 相比具有更强的抑制功能。
通过多色流式细胞术分析 SLE 患者外周血 CD4 T 细胞中 Foxp3 和 Helios 的表达，与健康对照（HC）、系统性硬皮病（SSc）和类风湿关节炎（RA）患者进行比较。通过流式细胞术分析细胞因子产生、CXCR3 和 CCR4 趋化因子受体表达、基础信号转导和转录激活因子 5（STAT5）a 磷酸化水平以及 T 细胞受体（TCR）Vβ 库，实时 PCR 分析 Foxp3 基因座的甲基化状态（Treg 特异性去甲基化区，TSDR）。
与 Foxp3(+)Helios(-)T 细胞不同，SLE 患者的 Foxp3(+)Helios(+)Treg 频率显著增加，且与疾病活动度呈正相关，而 SSc 和 RA 患者则未发生改变。与 HC 相比，SLE 患者中的 Foxp3(+)Helios(+)Treg 主要表现为 CD45RA(-)/CD31(-)/FoxP3(low)记忆表型，Ki-67 表达增加，基础 pSTAT5a 水平升高，TCR 库受限。尽管如此，与 HC 相似，SLE 中的 Foxp3(+)Helios(+)Treg 缺乏效应细胞因子产生，具有高度去甲基化的 TSDR，并表达相似水平的 CXCR3 和 CCR4。
我们的数据表明，在活跃的 SLE 中，具有功能抑制能力和向炎症组织迁移潜力的表达 Helios 的 Foxp3(+)Treg 被扩增，可能是通过 γ 链信号细胞因子和 TCR 刺激来代偿自身反应性效应反应。
