Johnson Susan, Eller Michael, Teigler Jeffrey E, Maloveste Sebastien M, Schultz Bruce T, Soghoian Damien Z, Lu Richard, Oster Alexander F, Chenine Agnès-Laurence, Alter Galit, Dittmer Ulf, Marovich Mary, Robb Merlin L, Michael Nelson L, Bolton Diane, Streeck Hendrik
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
J Virol. 2015 Aug;89(15):7494-505. doi: 10.1128/JVI.00438-15. Epub 2015 May 13.
CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection.
The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology.
CD4+ T细胞在慢性病毒感染的控制中起关键作用。最近,已描述了辅助效应之外的非传统CD4+ T细胞功能,并有人提出溶细胞性CD4+ T细胞在HIV感染控制中发挥作用。我们在此定义了HIV特异性溶细胞性CD4+ T细胞的转录、表型和功能特征。对HIV特异性溶细胞性CD4+ T细胞进行的Fluidigm BioMark和多参数流式细胞术分析显示,与Th1 CD4+细胞相比,其转录特征明显不同,但与HIV特异性溶细胞性CD8+ T细胞具有相似特征。此外,HIV特异性溶细胞性CD4+ T细胞相对于HIV特异性CD8+ T细胞表现出相当的杀伤活性,并在清除病毒感染细胞中协同发挥作用。有趣的是,我们发现溶细胞性CD4+ T细胞在急性HIV感染早期出现,并紧密跟随急性病毒载量轨迹。这种出现与早期病毒设定点相关,表明尽管CD4 T细胞易受HIV感染,但它参与了早期控制。我们的数据表明,溶细胞性CD4+ T细胞是一个独立于Th1细胞的亚群,在HIV感染的长期控制中与CD8+ T细胞表现出联合活性。
免疫系统控制慢性HIV感染的能力对疫苗设计和治疗方法都至关重要。许多研究都集中在CD8+ T细胞控制病毒能力的影响上,而CD4+ T细胞由于优先被感染,在HIV控制中作为效应细胞一直被忽视。我们在此表明,HIV特异性CD4+ T细胞的一个亚群在HIV复制的溶细胞控制中发挥协同作用。此外,这些细胞代表了CD4+ T细胞的一个独特亚群,与HIV特异性Th1细胞相比,表现出显著的转录和表型差异,但与CD8+ T细胞有相似之处。这些发现对于我们理解HIV免疫病理学很重要。