Kubota R, Nagai M, Kawanishi T, Osame M, Jacobson S
Viral Immunology Section, NIB, NINDS, NIH, Bethesda, Maryland 20892, USA.
AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1705-9. doi: 10.1089/08892220050193182.
Less than 1% of individuals infected with the human T lymphotropic virus type 1 (HTLV-1) develop an inflammatory neurological disorder, termed HTLV-1-associated myelopathy/tropical spastic (HAM/TSP), while the vast majority of those infected remain asymptomatic HTLV-1 carriers (ACs). The fundamental viroimmunological differences between these groups are not well understood. To address this issue, we have investigated HTLV-1-specific T cell responses and measured the proviral load in these groups. Frequencies of HTLV-1-specific CD8(+) cells were demonstrated to be significantly higher in HAM/TSP patients than in ACs by using intracellular cytokine staining and soluble divalent HLA-A2/Ig fusion protein loaded with HTLV-1 Tax 11-19 peptide. It is consistent with the observed increase in HTLV-1-specific cytotoxic T lymphocytes in HAM/TSP patients. These CD8(+) cells produced interferon (IFN)-gamma in recognition of HTLV-1 antigens bound to HLAs on the infected CD4(+) cells. Using phenotypic markers indicative for T cell differentiation, memory and/or effector HTLV-1 Tax-specific CD8(+) cells were found to be increased in HLA-A2 HAM/TSP patients. HTLV-1 proviral load was elevated in HAM/TSP patients when compared to ACs. In addition, the proviral load in HAM/TSP patients correlated with the frequency of HTLV-1-specific IFN-gamma(+)CD8(+) cells or Tax-HLA-A2/Ig(+)CD8(+) cells, especially with the effector cells. In contrast, the proviral load inversely correlated with memory cells. These results suggest that HTLV-1 antigens may continuously stimulate HTLV-1-specific CD8(+) cells and differentiate them from memory cells into effector cells in vivo. These differentiated HTLV-1-specific CD8(+) cells may play a role in the pathogenesis of HAM/TSP.
感染1型人类嗜T淋巴细胞病毒（HTLV-1）的个体中，不到1%会患上一种炎症性神经疾病，称为HTLV-1相关脊髓病/热带痉挛性截瘫（HAM/TSP），而绝大多数感染者仍是无症状的HTLV-1携带者（ACs）。目前尚不清楚这些群体之间在病毒免疫学上的根本差异。为了解决这个问题，我们研究了HTLV-1特异性T细胞反应，并测量了这些群体中的前病毒载量。通过细胞内细胞因子染色和加载有HTLV-1 Tax 11-19肽的可溶性二价HLA-A2/Ig融合蛋白，发现HAM/TSP患者中HTLV-1特异性CD8(+)细胞的频率显著高于ACs。这与在HAM/TSP患者中观察到的HTLV-1特异性细胞毒性T淋巴细胞增加是一致的。这些CD8(+)细胞在识别与感染的CD4(+)细胞上的HLA结合的HTLV-1抗原时会产生干扰素（IFN）-γ。使用指示T细胞分化、记忆和/或效应的表型标记，发现HLA-A2 HAM/TSP患者中HTLV-1 Tax特异性CD8(+)细胞增加。与ACs相比，HAM/TSP患者的HTLV-1前病毒载量升高。此外，HAM/TSP患者的前病毒载量与HTLV-1特异性IFN-γ(+)CD8(+)细胞或Tax-HLA-A2/Ig(+)CD8(+)细胞的频率相关，尤其是与效应细胞相关。相反，前病毒载量与记忆细胞呈负相关。这些结果表明，HTLV-1抗原可能在体内持续刺激HTLV-1特异性CD8(+)细胞，并使它们从记忆细胞分化为效应细胞。这些分化的HTLV-1特异性CD8(+)细胞可能在HAM/TSP的发病机制中起作用。
