PDF(Pubmed)
Abstract：
Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.
摘要：
人类1型T细胞白血病病毒（HTLV-1）前病毒载量（PVL）增加是HTLV-1相关脊髓病/热带痉挛性轻瘫（HAM/TSP）的重要危险因素。关于HTLV-1特异性细胞毒性T淋巴细胞（CTL）对HAM/TSP患者有益还是有害存在争议。最近,HTLV-1Tax301-309已被鉴定为限于HLA-A*2402的免疫显性表位。我们使用152名HAM/TSP患者和155名无症状HTLV-1携带者的血液样本，调查了HLA-A*24是否降低HTLV-1PVL和HAM/TSP的风险。HAM/TSP患者的HLA-A*24等位基因频率高于无症状HTLV-1携带者（72.4％vs.58.7%,赔率比1.84)，与阴性患者相比，HLA-A*24阳性患者的HTLV-1PVL减少了42％。此外，PVL与税收301-309特定CTL的频率呈负相关。这些发现与降低HTLV-1PVL和HAM/TSP风险的HLA-A*02的作用相反。因此,我们比较了Tax11-19或Tax301-309特异性CTL的功能,这两种抗原表位分别局限于HLA-A*0201或HLA-A*2402.这些CTL的最大反应在IFN-γ和MIP-1β的产生或在细胞毒性分子脱粒的CD107a-a标志物的表达中没有差异。然而,税务301-309特异性CTL的T细胞亲和力比税务11-19特异性CTL高50倍，提示在低表达水平的抗原更好的抗原识别。这些结果表明，HLA-A*24，其诱导敏感的HTLV-1特异性CTL，尽管降低了HTLV-1PVL，但增加了HAM/TSP的风险。
