Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Hum Immunol. 2011 Nov;72(11):1001-6. doi: 10.1016/j.humimm.2011.07.308. Epub 2011 Aug 2.
Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A0201 tetramer and an HTLV-1 Tax/HLA-A2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1.
人类 T 淋巴细胞白血病病毒 1（HTLV-1）可导致 HTLV-1 相关脊髓病/热带痉挛性截瘫（HAM/TSP）和成人 T 细胞白血病/淋巴瘤，发生于免疫功能障碍的个体。在这项研究中，为了描述无症状 HTLV-1 携带者（AC）、HAM/TSP 患者和伴有自身免疫性疾病的携带者（CAIDs）中 HTLV-1 特异性细胞毒性 T 淋巴细胞（CTL）群体，我们使用 HTLV-1 Tax/HLA-A0201 四聚体和 HTLV-1 Tax/HLA-A2402 四聚体来研究程序性死亡-1 及其配体（PD-1/PD-L1）在 HTLV-1 特异性 CTL 功能中的作用。有趣的是，AC 中 HTLV-1 Tax301-309/HLA-A2402 四聚体（+）CD8（+）细胞表达 PD-1 的比例明显高于 HTLV-1 Tax11-19/HLA-A0201 四聚体（+）CD8（+）细胞表达 PD-1 的比例。与 AC 相比，HAM/TSP 中 HTLV-1 特异性 CTL 上 PD-1 的表达显著下调。在未经刺激的 AC 淋巴细胞中观察到 PD-L1 的表达，并且在短期培养后，AC 中的 PD-L1 表达大于 HAM/TSP 和 CAIDs。此外，在 HAM/TSP 中 CTL 脱颗粒受损，而抗 PD-L1 阻断可显著增加 AC 中的 CTL 功能。HAM/TSP 中 HTLV-1 特异性 CTL 上 PD-1 的下调和 PD-L1 的表达缺失，以及 HAM/TSP 中 HTLV-1 特异性 CTL 功能受损，可能是针对 HTLV-1 的明显功能障碍的免疫反应的基础。
