University of Alabama at Birmingham, Department of Medicine, Birmingham, AL 35294, USA.
J Virol. 2011 Mar;85(5):2316-24. doi: 10.1128/JVI.01476-10. Epub 2010 Dec 15.
A hallmark of human immunodeficiency virus type 1 (HIV-1) pathogenesis is the rapid loss of CD4 T cells leading to generalized immune dysfunction, including an exhausted CD8 T cell phenotype. Understanding the necessary factors that govern the functional quality and protective potential of antiviral T cell responses would facilitate rational vaccine design and improve therapeutic strategies to combat persistent infections. Mouse models of chronic viral infection demonstrate that interleukin-21 (IL-21), produced primarily by CD4 T cells, is required for the generation and maintenance of functionally competent CD8 T cells and viral containment. We reasoned that preserved IL-21 production during HIV-1 infection would be associated with enhanced CD8 T cell function, allowing improved viral control. Here we analyzed the ability of CD4 and CD8 T cells to produce several cytokines in addition to IL-21 ex vivo following stimulation with overlapping HIV-1 peptides. Both CD4 and CD8 T cells were able to produce IL-21 in response to HIV-1 infection, with the latter cell type more closely associated with viral control. Furthermore, IL-21-producing HIV-1-specific CD4 T cells (compared to those producing other cytokines) were the best indicator of functional CD8 T cells. Our results demonstrate that HIV-1-specific IL-21-producing CD8 T cells are induced following primary infection and enriched in elite controllers, suggesting a critical role for these cells in the maintenance of viremia control.
人类免疫缺陷病毒 1 型（HIV-1）发病的一个标志是 CD4 T 细胞的迅速丧失，导致广泛的免疫功能障碍，包括耗尽的 CD8 T 细胞表型。了解控制抗病毒 T 细胞反应的功能质量和保护潜力的必要因素将有助于合理的疫苗设计，并改善治疗策略以对抗持续感染。慢性病毒感染的小鼠模型表明，白细胞介素 21（IL-21），主要由 CD4 T 细胞产生，是产生和维持功能成熟的 CD8 T 细胞和病毒控制所必需的。我们推断，在 HIV-1 感染期间保留 IL-21 的产生将与增强的 CD8 T 细胞功能相关，从而允许改善病毒控制。在这里，我们分析了 CD4 和 CD8 T 细胞在体外用重叠的 HIV-1 肽刺激后除了产生 IL-21 之外，还能产生几种细胞因子的能力。CD4 和 CD8 T 细胞都能够对 HIV-1 感染产生 IL-21，后者与病毒控制更密切相关。此外，产生 IL-21 的 HIV-1 特异性 CD4 T 细胞（与产生其他细胞因子的细胞相比）是功能性 CD8 T 细胞的最佳指标。我们的结果表明，HIV-1 特异性 IL-21 产生的 CD8 T 细胞在初次感染后被诱导，并在精英控制器中富集，这表明这些细胞在维持病毒血症控制中起着关键作用。
