Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease
Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease
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DOI：
10.1182/blood-2008-02-138529
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发表时间：
2008-09-15
期刊：
影响因子：
20.3
通讯作者：
Jacobson, Steven
中科院分区：
文献类型：
--
作者：
Enose-Akahata, Yoshimi;Oh, Unsong;Jacobson, Steven
CD 8（+）T细胞在人类嗜T淋巴细胞病毒I型（HTLV-I）相关性脊髓病/热带痉挛性轻瘫（HAM/TSP）的中枢神经系统炎症中起作用。我们分析了CD 8（+）T细胞功能障碍（脱颗粒和IFN-γ产生），并证明HAM/TSP患者（HAM/TSP患者）的CD 8（+）T细胞在离体非刺激培养物中自发脱颗粒并表达IFN-γ。HTLV-I无症状携带者和健康供体的CD 8（+）T细胞则没有。在Tax 11 -19/HLA-A*201四聚体（+）细胞中检测到自发脱颗粒，但在CMV pp 65四聚体（+）细胞中未检测到自发脱颗粒。有趣的是，与HAM/TSP患者的自体CD 14（+）细胞共培养可诱导CD 8（+）T细胞的脱粒和IFN-γ产生，而与感染患者的CD 14（+）细胞中的前病毒DNA载量相关，但与HAM/TSP患者的自体CD 4（+）T细胞不共培养。HAM/TSP患者CD 14（+）细胞表面IL-15的表达增强，IL-15可诱导感染患者的脱颗粒和IFN-γ的产生。MHC I类和IL-15的阻断证实了这些结果。因此，HAM/TSP患者的CD 8（+）T细胞失调是由病毒感染和CD 14（+）细胞上IL-15增强介导的。尽管病毒表达低于CD 4（+）T细胞，但HTLV-1感染或活化的CD 14（+）细胞可能是迄今为止重要的但未被认识的储库，特别是在HAM/TSP患者中。
CD8(+) T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8(+) T- cell dysfunction (degranulation and IFN-gamma production) and have demonstrated that CD8(+) T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-gamma in ex vivo unstimulated culture. CD8(+) T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer(+) cells, but not in CMV pp65 tetramer(+) cells. Interestingly, degranulation and IFN-gamma production in CD8(+) T cells was induced by coculture with autologous CD14(+) cells, but not CD4(+) T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14(+) cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-gamma production in infected patients, was enhanced on surface of CD14(+) cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8(+) T- cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14(+) cells in HAM/TSP patients. Despite lower viral expression than in CD4(+) T cells, HTLV-I-infected or -activated CD14(+) cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.