Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1.
Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1.
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DOI：
10.1007/s10875-013-9918-x
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发表时间：
2013-10
影响因子：
9.1
通讯作者：
Jain P
中科院分区：
文献类型：
--
作者：
Manuel SL;Sehgal M;Connolly J;Makedonas G;Khan ZK;Gardner J;Betts MR;Jain P
与人类T细胞白血病病毒1型(HTLV-1)相关的衰弱神经退行性疾病和肿瘤性疾病的免疫病理机制尚不完全清楚。在这方面，来自HTLV-1流行区的患者队列包括血清阴性对照(对照组)、无症状携带者(ACS)和成人T细胞白血病(ATL)或HTLV相关性脊髓病/热带痉挛麻痹(HAM/TSP)患者，分析了CD8+T细胞多功能性对病毒抗原税的反应。与急性冠脉综合征相比，ATL和HAM/TSP患者对Tax反应的CTL频率和多功能性较低，提示这些患者存在CD8+T细胞功能障碍。作为一种潜在的机制，程序性死亡-1(PD-1)受体在ATL和HAM/TSP的税收反应和总CD8+T细胞中高度不受调节，而在ACS中不表达，并与这些人缺乏多功能直接相关。此外，PD-1的表达显示出直接的，而丝裂原蛋白-1的α的表达与前病毒负荷有间接的相关性，这为研究HTLV相关疾病的免疫发病机制提供了新的见解。此外，我们通过Luminex试验确定了定义临床样本免疫激活状态的关键细胞因子信号。总之，我们的研究结果表明，重建全功能的CTL，刺激MIP-1α的表达，和/或阻断PD-1途径，是针对HTLV介导的疾病的免疫治疗和治疗性疫苗的潜在途径。
The immunopathogenic mechanisms responsible for debilitating neurodegenerative and oncologic diseases associated with human T-cell leukemia virus type 1 (HTLV-1) are not fully understood. In this respect, a patient cohort from HTLV-1 endemic region that included seronegative controls (controls), asymptomatic carriers (ACs), and patients with adult T-cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was analyzed for CD8+ T cells polyfunctionality in response to the viral antigen Tax. Compared to ACs, ATL and HAM/TSP patients had lower frequency and polyfunctionality of CTLs in response to Tax suggesting dysfunction of CD8+ T cells in these individuals. As an underlying mechanism, programmed death-1 (PD-1) receptor was found to be highly unregulated in Tax-responsive as well as total CD8+ T cells from ATL and HAM/TSP but not from ACs and directly correlated with the lack of polyfunctionality in these individuals. Further, PD-1 expression showed a direct whereas MIP-1α expression had an indirect correlation with the proviral load providing new insights about the immunopathogenesis of HTLV-associated diseases. Additionally, we identified key cytokine signatures defining the immune activation status of clinical samples by the luminex assay. Collectively, our findings suggest that reconstitution of fully functional CTLs, stimulation of MIP-1α expression, and/or blockade of the PD-1 pathway are potential approaches for immunotherapy and therapeutic vaccine against HTLV-mediated diseases.