Division of Infectious Diseases, Ottawa Hospital-General Campus, 501 Smyth Rd., Ottawa, Ontario, Canada.
J Leukoc Biol. 2011 Apr;89(4):499-506. doi: 10.1189/jlb.0710430. Epub 2010 Dec 21.
This study tests the hypothesis that IL-7 signaling and activity of CD8(+) T cells are impaired in HIV infection. IL-7 is necessary for optimal CTL activity and T cell survival and proliferation. Defects in IL-7R signaling may contribute to impaired activity of IL-7 observed in progressive HIV disease. A decreased proportion of CD8(+) T cells expressing the IL-7Rα chain (CD127) in progressive HIV disease would be expected to affect IL-7 activity. Alternatively, disease-associated defects of remaining CD8(+)CD127(+) T cells may influence IL-7 responsiveness. Therefore, the IL-7 responsiveness of CD8(+)CD127(+) T cells from HIV(-) and untreated or treated HIV(+) individuals was investigated. Blood was collected from HIV(-) and untreated or effectively treated HIV(+) (<50 viral copies/ml for >1 year) individuals, and CD8(+)CD127(+) T cells were isolated and cultured with IL-7. Indicators of IL-7 signaling (P-STAT5) and activity (Bcl-2 and proliferation) were evaluated by flow cytometry. Isolated CD8(+)CD127(+) T cells from untreated HIV(+) individuals expressed significantly less P-STAT5 in response to IL-7 compared with CD8(+)CD127(+) T cells from HIV(-) individuals. In effectively treated HIV(+) individuals, CD8(+)CD127(+) T cells also expressed significantly lower levels of P-STAT5 compared with HIV(-) individuals. IL-7-dependent proliferation of CD8(+)CD127(+) T cells from untreated HIV(+) individuals was similarly impaired. In contrast, IL-7-induced Bcl-2 expression was not impaired in CD8(+)CD127(+) T cells from HIV(+) individuals. These data demonstrate that IL-7/IL-7R dysfunction in HIV infection may contribute to IL-7-specific signaling defects. Decreased, IL-7-dependent activation of STAT5 and impaired proliferation may negatively impact the maintenance of CD8(+) T cell responsiveness in HIV infection.
本研究旨在验证假说，即 HIV 感染会导致白细胞介素 7（IL-7）信号转导和 CD8+T 细胞活性受损。IL-7 对于 CTL 活性和 T 细胞存活与增殖至关重要。IL-7R 信号转导缺陷可能导致 HIV 进展性疾病中观察到的 IL-7 活性受损。在进展性 HIV 疾病中，预期表达 IL-7Rα链（CD127）的 CD8+T 细胞比例降低，这将影响 IL-7 活性。或者，与疾病相关的剩余 CD8+CD127+T 细胞缺陷可能影响 IL-7 反应性。因此，研究了来自 HIV（-）和未经治疗或经有效治疗的 HIV（+）个体的 CD8+CD127+T 细胞对 IL-7 的反应性。从 HIV（-）和未经治疗或经有效治疗的 HIV（+）（>1 年，病毒载量<50 拷贝/ml）个体中采集血液，并分离和培养 CD8+CD127+T 细胞，同时加入 IL-7。通过流式细胞术评估 IL-7 信号转导（P-STAT5）和活性（Bcl-2 和增殖）的标志物。与 HIV（-）个体的 CD8+CD127+T 细胞相比，未经治疗的 HIV（+）个体的 CD8+CD127+T 细胞对 IL-7 的反应中，P-STAT5 的表达显著降低。在经有效治疗的 HIV（+）个体中，与 HIV（-）个体相比，CD8+CD127+T 细胞中 P-STAT5 的表达水平也显著降低。未经治疗的 HIV（+）个体的 CD8+CD127+T 细胞增殖也受到类似的 IL-7 依赖性损害。相比之下，HIV 感染个体的 CD8+CD127+T 细胞中，IL-7 诱导的 Bcl-2 表达不受损害。这些数据表明，HIV 感染中 IL-7/IL-7R 功能障碍可能导致 IL-7 特异性信号缺陷。STAT5 的 IL-7 依赖性激活和增殖受损可能会对 HIV 感染中 CD8+T 细胞反应性的维持产生负面影响。
