Role of CD8+CD25+Foxp3+Regulatory T Cells in Multiple Sclerosis
Role of CD8+CD25+Foxp3+Regulatory T Cells in Multiple Sclerosis
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DOI：
10.1002/ana.21944
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发表时间：
2010-05-01
影响因子：
11.2
通讯作者：
Villa, Andres
中科院分区：
文献类型：
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作者：
Correale, Jorge;Villa, Andres
目的：本研究的目的是探讨CD8+ CD25+ FoxP3+细胞在多发性硬化症（MS）病程中的作用。方法：从20例MS加重期患者、15例缓解期患者、15例健康者和10例其他炎性神经系统疾病患者的外周血和脑脊液（CSF）中分离识别自身反应性CD4+ T细胞的CD8+ T细胞克隆（TCCs）。研究了非细胞毒性CD8+ CD25+调节性T细胞的特性。采用流式细胞术评价细胞表型。采用酶联免疫吸附法测定细胞因子产量和磷酸化信号转导因子及转录激活因子3 （STAT3）浓度。为了评估树突状细胞（dc）的2,3-双加氧酶（IDO）活性，采用高效液相色谱法测定犬尿氨酸浓度。结果：加入CD8+ CD25+ FoxP3+细胞后，观察到CD4+自身反应性t细胞增殖、干扰素γ和白细胞介素(IL)-17分泌受到抑制。使用小干扰RNA沉默FoxP3可消除抑制。细胞为CD122+、CTLA-4+、GITR+、CCR7+和CD62L+，产生IL-10和转化生长因子p。CD8+ CD25+ FoxP3+细胞通过STAT3介导的途径下调树突状细胞上共刺激分子的表达，导致抗原呈递效率降低，并通过STAT3和细胞毒性t淋巴细胞抗原4依赖机制诱导dc上IDO的表达。在血液和脑脊液中研究的CD8+调节性TCC克隆频率在加重期比缓解期或对照组受到更大程度的抑制。同样，在MS患者急性加重期的脑脊液中，流式细胞术检测到CD8+ CD25+ FoxP3+ T细胞水平较低。解释：CD8+ CD25+ FoxP3+细胞是一种新的调节细胞，在MS过程中对自身反应性CD4+ T细胞的调节有重要影响，诱导这些细胞可能通过消除或抑制自身反应性T细胞为MS提供新的治疗选择。神经网络学报，2010；67:625 - 638
Objective: The objective of this study was to investigate the role of CD8+ CD25+ FoxP3+ cells during the course of multiple sclerosis (MS).Methods: Peripheral blood and cerebrospinal fluid (CSF) CD8+ T-cell clones (TCCs) recognizing autoreactive CD4+ T cells were isolated from 20 MS patients during exacerbations, 15 patients in remission, 15 healthy subjects, and 10 patients with other inflammatory neurological diseases. Characteristics of noncytotoxic CD8+ CD25+ regulatory T cells were studied. Cell phenotype was evaluated using flow cytometry. Cytokine production and phospho-signal transducer and activator of transcription 3 (STAT3) concentration were determined using enzyme-linked immunosorbent assay. To assess 2,3-dioxygenase (IDO) activity on dendritic cells (DCs), kynurenine concentration was measured by high-performance liquid chromatography.Results: Inhibition of CD4+ self-reactive T-cell proliferation, and of interferon-gamma and interleukin (IL)-17 secretion, was observed after adding CD8+ CD25+ FoxP3+ cells to cultures. Suppression was abrogated by silencing FoxP3 using small interfering RNA. Cells were CD122+, CTLA-4+, GITR+, CCR7+, and CD62L+, producing IL-10 and transforming growth factor-p. CD8+ CD25+ FoxP3+ cells downregulated costimulatory molecule expression on dendritic cells through a STAT3-mediated pathway, resulting in less efficient antigen presentation, and induced IDO expression on DCs through STAT3 and cytotoxic T-lymphocyte antigen 4-dependent mechanisms. CD8+ regulatory TCC cloning frequency studied in blood and CSF was suppressed to a greater degree during exacerbations than during remission or in controls. Likewise, in CSF of MS patients during acute exacerbations, lower levels of CD8+ CD25+ FoxP3+ T cells were detected using flow cytometry.Interpretation: CD8+ CD25+ FoxP3+ cells are novel regulatory cells exerting significant influence over self-reactive CD4+ T-cell regulation during the course of MS. Induction of these cells may provide new therapeutic alternatives for MS by eliminating or inhibiting self-reactive T cells. ANN NEUROL 2010;67:625-638