The interleukin-7 receptor α chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis
The interleukin-7 receptor α chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis
复制标题
DOI：
10.1002/eji.201041139
复制
发表时间：
2011-03-01
影响因子：
5.4
通讯作者：
Wildemann, Brigitte
中科院分区：
文献类型：
--
作者：
Haas, Juergen;Korporal, Mirjam;Wildemann, Brigitte
多发性硬化症（MS）患者Treg体内平衡受到干扰。最近胸腺迁移(RTE)-Treg的频率降低，RTE-Treg和长期记忆Treg之间的差异与ms相关的Treg缺陷一致，如前所述。最近的研究表明，IL-7和胸腺基质淋巴生成素（TSLP）对Treg成熟至关重要。因此，通过它们的受体（IL-7R， TSLP受体（TSLPR）），共享IL-7R α链（IL-7R α）的信号改变可能导致Treg发育受损。使用56名MS患者和33名健康对照者的血液样本，我们评估了IL-7R α在常规T细胞上的表达；Treg的频率、表型和抑制活性、血浆IL-7和可溶性IL-7R α水平；筛选ms相关IL-7RA基因多态性rs6897932。此外，我们确定了表达两种不同的TCR V α链的Treg，它们代表胸腺起源的细胞。由于胸腺髓样树突状细胞（MDCs）中的TSLP/TSLPR信号促进Treg分化，我们测量了外周MDCs中的TSLPR表达，以间接测试TSLPR表达改变是否会增加Treg新生受损。我们发现常规T细胞中IL-7R α表达降低，IL-7血浆水平上调，MS中RTE-Treg频率和Treg功能降低，没有明显的遗传影响。MS中IL-7R α表达降低与双受体Treg和MDC TSLPR表达降低相关，表明胸腺Treg输出收缩。我们认为，IL-7R/TSLPR信号的改变有助于MS中Treg新生受损，这通过扩大记忆-Treg来补偿，最终导致Treg功能失调。
Treg homeostasis is disturbed in multiple sclerosis (MS). Frequencies of recent thymic emigrant (RTE)-Treg are reduced and the disparity between RTE-Treg and long-lived memory Treg coincides with the MS-associated Treg defect, as shown previously. Recent studies demonstrate that IL-7 and thymic stromal lymphopoietin (TSLP) are critical for Treg maturation. Therefore, altered signaling through their receptors (IL-7R, TSLP receptor (TSLPR)), sharing the IL-7R alpha-chain (IL-7R alpha), might contribute to impaired Treg development. Using blood samples from 56 patients with MS and 33 healthy controls, we assessed IL-7R alpha-expression on conventional T cells; frequencies, phenotypes and suppressive activities of Treg, plasma levels of IL-7 and soluble IL-7R alpha; and screened for MS-associated IL-7RA gene polymorphism rs6897932. Moreover, we determined Treg expressing two different TCR V alpha-chains designating thymus-originated cells. As TSLP/TSLPR signaling in thymic myeloid dendritic cells (MDCs) promotes Treg differentiation, we measured TSLPR expression on peripheral MDCs to indirectly test whether altered TSLPR expression might add to compromised Treg neogenesis. We found reduced IL-7R alpha expression on conventional T cells and upregulated IL-7 plasma levels together with reduction of RTE-Treg frequencies and Treg function in MS, without clear genetic influence. Decreased IL-7R alpha expression in MS correlated with declined dual-receptor-Treg and reduced MDC TSLPR expression, indicating contracted thymic Treg output. We suggest that altered IL-7R/TSLPR signaling contributes to impaired Treg neogenesis in MS, which is compensated by expanded memory-Treg and finally results in dysfunctional Treg.