HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals
HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals
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DOI：
10.1186/1742-4690-9-46
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发表时间：
2012-05-30
期刊：
影响因子：
3.3
通讯作者：
Matsuoka, Masao
中科院分区：
文献类型：
--
作者：
Satou, Yorifumi;Utsunomiya, Atae;Matsuoka, Masao
背景：HTLV-1以CD4T细胞为主要宿主细胞，通过感染的CD4(+)T细胞的克隆性增殖维持前病毒载量。因此，HTLV-1感染CD4(+)T细胞被认为在HTLV-1相关致病中起关键作用，包括CD4(+)T细胞的白血病/淋巴瘤和慢性炎症性疾病。最近，有报道称一部分HTLV-1感染的CD4(+)T细胞表达FoxP3，FoxP3是调节性T细胞的主要分子。结果：采用流式细胞术分析了23例HTLV-1感染的无症状携带者(AC)、10例HTLV-1相关性脊髓病/热带痉挛截瘫(HAM/TSP)患者、10例成人T细胞白血病(ATL)患者和10例健康献血员外周血单个核细胞(PBMC)中HTLV-1感染情况，以探讨HTLV-1感染对T细胞亚群的影响。前病毒载量高的AC、HAM/TSP或ATL患者的CD4(+)T细胞中FoxP3(+)细胞的比例明显高于非感染者。前病毒载量与FoxP3(+)的CD4(+)T细胞百分比呈正相关。CD4(+)FoxP3(+)T细胞本身也经常感染HTLV-1。我们的结论是，在慢性感染过程中，FoxP3(+)T细胞不成比例地感染HTLV-1。接下来，我们关注HAM/TSP患者的PBMC。T-reg相关分子CTLA-4和GITR在CD4(+)FoxP3(+)T细胞中的表达水平降低。进一步通过CD45RA和FoxP3染色鉴定FoxP3(+)CD4(+)T细胞亚群，发现CD45RA-FoxP3(低)非抑制性T细胞增加。这些发现可以协调HAM/TSP的炎症表型和观察到的FoxP3(+)细胞频率的增加。结论：HTLV-1感染可导致FoxP3(+)CD4(+)T细胞频率和表型异常。
Background: HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4(+) T cells. Infection of CD4(+) T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4(+) T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4(+) T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression.Results: To investigate the effect of HTLV-1 infection on CD4(+) T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs) of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC), 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), 10 patients with adult T-cell leukemia (ATL), and 10 healthy donors. The frequency of FoxP3(+) cells in CD4(+) T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4(+) T cells that were FoxP3(+). The CD4(+)FoxP3(+) T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3(+) T-cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the T-reg associated molecules CTLA-4 and GITR were decreased in CD4(+)FoxP3(+) T cells. Further we characterized FoxP3(+)CD4(+) T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA-FoxP3(low) non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3(+) cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression but also wide variation in FoxP3 expression level among individual cases.Conclusions: HTLV-1 infection induces an abnormal frequency and phenotype of FoxP3(+)CD4(+) T cells.