Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus
Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus
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DOI：
10.1136/annrheumdis-2012-202216
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发表时间：
2013-09-01
影响因子：
27.4
通讯作者：
Hiepe, Falk
中科院分区：
文献类型：
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作者：
Alexander, Tobias;Sattler, Arne;Hiepe, Falk
目的最近的数据争论的Helios，Ikaros家族成员，作为胸腺源性调节性T细胞（Treg）的标志物的适用性。然而，Foxp 3（+）Helios（+）Treg可能在慢性自身免疫如系统性红斑狼疮（SLE）中介导免疫耐受中特别相关，因为与Foxp 3（+）Helios（-）Treg相比，它们具有增强的抑制功能。与健康对照（HC）和系统性硬化症（SSc）和类风湿性关节炎（RA）患者相比。通过流式细胞术分析细胞因子产生、CXCR 3和CCR 4的趋化因子受体表达、基础信号转导子和转录激活子5（STAT 5）α磷酸化水平和T细胞受体（TCR）V库，并通过流式细胞术分析Foxp 3基因座的甲基化状态。结果Foxp 3（+）Helios（+）Treg的频率，与Foxp 3（+）Helios（-）T细胞不同，在SLE患者中显著增加，并与疾病活动呈正相关，而在SSc和RA患者中无变化。与HC相比，SLE患者的Foxp 3（+）Helios（+）Treg主要表现为CD 45 RA（-）/CD 31（-）/FoxP 3（低）记忆表型，Ki-67表达增加，基础pSTAT 5a水平升高，TCR库受限。尽管如此，与HC相似，SLE中Foxp 3（+）Helios（+）Treg缺乏效应细胞因子的产生，具有高度去甲基化的TSDR，并且表达相当水平的CXCR 3和CCR 4。结论我们的数据表明，表达Helios的Foxp 3（+）Treg具有功能抑制能力和迁移到炎症组织中的潜力，在活动性SLE中扩增，推测是通过-链信号传导细胞因子和TCR刺激。以补偿自身反应性效应器反应。
ObjectivesRecent 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.MethodsMulticolour 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) V repertoire were analysed by flow cytometry, and the methylation status of the Foxp3 locus (Treg-specific demethylated region, TSDR) by real-time PCR.ResultsFrequencies 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.ConclusionsOur data suggest that Helios-expressing Foxp3(+) Treg with functional suppressive capacity and migratory potential into inflamed tissues are expanded in active SLE, presumably through -chain signalling cytokines and TCR stimulation, to compensate for autoreactive effector responses.