Laboratory of Innate Immunity, Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, Canada.
J Immunol. 2010 Jan 1;184(1):114-26. doi: 10.4049/jimmunol.0901967. Epub 2009 Nov 30.
IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4(+) T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4(+) T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4(+) T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4(+) T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21-producing HIV-specific, but not human CMV-specific, Ag-experienced CD4(+) T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4(+) T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.
IL-21 是一种新近发现的免疫增强细胞因子，在控制慢性病毒感染中发挥着重要作用。它主要由 CD4(+) T 细胞产生，而 CD4(+) T 细胞也是 HIV-1 的主要靶标，并且在 HIV 感染者中经常被耗尽。因此，我们试图确定 IL-21 的产生动态及其对 CD4(+) T 细胞存活和 HIV 特异性 CTL 频率的潜在影响。为此，我们对不同组别的 HIV 感染者进行了一系列横断面和纵向研究，并在本研究中表明，细胞因子的产生在感染早期就受到了损害。血清细胞因子浓度与感染者的 CD4(+) T 细胞计数相关。在不同组别的 HIV 感染者中，只有精英控制者维持正常的细胞因子产生。高效抗逆转录病毒疗法仅部分恢复了这种细胞因子的产生。有趣的是，HIV 感染人 CD4(+) T 细胞通过降低病毒感染细胞中 c-Maf 的表达而不是未感染旁观者细胞来抑制细胞因子的产生。我们还表明，HIV 特异性而非人类 CMV 特异性 Ag 经验的 IL-21 产生 CD4(+) T 细胞的频率在 HIV 感染的病毒血症患者中降低。此外，我们在本研究中证明，重组人 IL-21 可防止 HIV 感染患者的 CD4(+) T 细胞自发体外死亡增加。总之，我们的研究结果表明，血清 IL-21 浓度可以作为监测 HIV 疾病进展的有用生物标志物，并且该细胞因子可考虑用于 HIV 感染者的免疫治疗。
