在一小部分无症状人类 T 细胞白血病病毒 1 携带者中，Tax 特异性而非巨细胞病毒特异性 CD8+ T 淋巴细胞功能受损。
Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers.
机构信息
Department of Immunotherapeutics, Tokyo Medical and Dental University, Tokyo, Japan.
出版信息
Retrovirology. 2011 Dec 7;8:100. doi: 10.1186/1742-4690-8-100.
BACKGROUND
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8+ T-cells in various clinical status of HTLV-1 infection.
RESULTS
By using tetramers consisting of HLA-A0201, -A2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8+ T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8+ T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8+ T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8+ T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8+ T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8+ T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8+ T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8+ T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8+ T-cells.
CONCLUSIONS
These findings indicated that Tax-specific CD8+ T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8+ T-cells in early stages.
背景
人类 T 细胞白血病病毒 1 型（HTLV-1）在一小部分感染个体中导致成人 T 细胞白血病（ATL）和 HTLV-1 相关脊髓病/热带痉挛性截瘫（HAM/TSP）。ATL 通常与全身免疫抑制和 HTLV-1 特异性 T 细胞反应受损有关，这是一种重要的宿主防御系统。我们之前发现，一小部分无症状 HTLV-1 携带者（AC）已经表现出针对主要靶抗原 Tax 的受损 T 细胞反应。然而，这些个体中受损的 HTLV-1 Tax 特异性 T 细胞反应是 HTLV-1 特异性现象，还是仅仅反映全身免疫抑制尚不清楚。在这项研究中，为了表征受损的 HTLV-1 特异性 T 细胞反应，我们研究了 HTLV-1 感染的各种临床状态下 Tax 特异性 CD8+T 细胞的功能。
结果
通过使用由 HLA-A0201、-A2402 或 -A*1101 组成的四聚体和相应的 Tax 表位肽，我们在 87.0%（20/23）的 AC 和 100%（18/18）的 HAM/TSP 患者中检测到外周血中的 Tax 特异性 CD8+T 细胞。我们还在 38.1%（8/21）的慢性型 ATL（cATL）患者中检测到 Tax 特异性 CD8+T 细胞，尽管其在外周血 CD8+T 细胞中的频率明显低于 AC 或 HAM/TSP 患者。在 HAM/TSP 患者中检测到的 Tax 特异性 CD8+T 细胞在培养中增殖良好，并在受到 Tax 肽刺激时产生 IFN-γ。然而，在 cATL 患者中检测到的 Tax 特异性 CD8+T 细胞的这些功能严重受损。在 AC 中，大多数情况下保留了 Tax 特异性 CD8+T 细胞的反应。然而，我们发现一个 AC 样本的 Tax 特异性 CD8+T 细胞几乎不产生 IFN-γ，并且在响应 Tax 肽刺激时无法增殖和表达激活（CD69）和脱颗粒（CD107a）标志物。重要的是，同一个 AC 样本含有巨细胞病毒（CMV）pp65 特异性 CD8+T 细胞，这些细胞在受到 CMV pp65 肽刺激时具有功能。我们进一步检查了另外两名冒烟型 ATL 患者的样本，发现他们的 Tax 特异性而不是 CMV 特异性 CD8+T 细胞也存在功能障碍。
结论
这些发现表明，不仅在 ATL 患者中，而且在有限的 AC 人群中，Tax 特异性 CD8+T 细胞数量稀少且功能失调，并且在早期阶段这种功能失调是 HTLV-1 特异性 CD8+T 细胞的选择性。
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