Anergizing effect of NK cell receptor expression on HIV-specific CD8+ T cells

NK 细胞受体表达对 HIV 特异性 CD8 T 细胞的失活作用

• 批准号: 7558352
• 负责人: Galit Alter
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558352
• 关键词: Accounting; Activities of Daily Living; Address; Antiviral Agents; Bacterial Infections; C-Type Lectins; CD8 Antigens; CD8B1 gene; CD94 Antigen; Cell Death; Cell physiology; Cell secretion; Cells; Cellular biology; Chronic; Depth; Family; HIV; HIV-1; Human; Immune; Immunity; Infection; KLRA1 gene; Kinetics; Lead; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Numbers; Phenotype; Play; Population; Role; Signal Transduction; Staging; Surface; Surface Antigens; Synapses; T-Cell Activation; T-Lymphocyte; Transcriptional Activation; Up-Regulation; Viral; Virus; Virus Diseases; design; functional disability; improved; member; novel; receptor; receptor expression; receptor upregulation; reconstitution; response; tumor

Virus-specific-CD8+ T cells play a central role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. However despite the induction of strong and broad HIVspecific CD8+ T cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions. A number of recent studies have shown that a significant subset of CD8+ T cells appear to upregulate inhibitory "NK cell receptor" expression following encounter with antigen, and that CD8+ T cells expressing NK cell receptors persist in chronically infected mice but not in mice that clear the infection. These receptors included members of the KIR family, as well as of the C-type lectin family (NKG2) in humans and the Ly49 family in mice. The expression of these receptors on CD8+ T cells can have a profound effect on the functional capacity of both tumor-specific and virus-specific T cells. Recently, increased levels of KIR and NKG2A expression have also been described on discrete populations of CD8+ T cells in chronic HIV-1 infection. Given the profound inhibitory effect of these receptors, this proposal aims to gain a better understanding of the role of KIR and NKG2A receptor expression on HIV-1-specific CD8+ T cell function. In this application, the expression profile of both KIR and NKG2 receptors will be characterized on CD8+ T cells in subjects at different stages of HIV-1 infection to determine the kinetics of NK cell receptor upregulation in HIV-1 infection, to elucidate the impact of NK cell receptor expression on CD8+ T cell function, whether these receptors are preferentially enriched on the surface of HIV-specific CD8+ T cells, and whether this inhibitory effect can be reversed. Furthermore, the precise mechanisms accounting for NK cell receptor-mediated inhibition of CD8+ T cell activation will be characterized on the immunological synaptic level as well as the TCR signaling-cascade level. Thus this application aims to determine whether one of the mechanisms contributing to impaired CD8+ T cell activity during persistent viral infections may be due to an up-regulation of inhibitory NK cell receptors. These in depth studies geared towards understanding the underlying mechanism of KIR/NKG2A inhibitory activity on CD8+ T cells will certainly contribute to the field of basic CD8+ T cell biology and potentially allow for the identification of novel targets to reconstitute effective of CD8+ T cell immunity in the setting of chronic infections, such as HIV.

病毒特异性-CD 8 + T细胞通过直接消除感染的CD 8 + T细胞在控制病毒感染中发挥核心作用。 细胞和分泌的一些可溶性因子。然而，尽管诱导了强大和广泛的艾滋病毒特异性， 慢性HIV-1感染中的CD 8 + T细胞应答，这些细胞逐渐失去关键效应子 功能协调发展的最近的一些研究表明，一个重要的CD 8 + T细胞亚群似乎上调， 与抗原接触后抑制性“NK细胞受体”表达，以及CD 8 + T细胞 表达NK细胞受体的小鼠在慢性感染中持续存在，但在清除感染的小鼠中不存在。 这些受体包括KIR家族的成员，以及C型凝集素家族（NKG 2）的成员。 人类和小鼠中的Ly 49家族。这些受体在CD 8 + T细胞上的表达可以具有调节作用。 对肿瘤特异性T细胞和病毒特异性T细胞的功能能力都有深远的影响。最近， 在CD 8 + T细胞的离散群体中也描述了KIR和NKG 2A表达水平的增加， 慢性HIV-1感染的细胞。考虑到这些受体的深刻抑制作用，该提案旨在 更好地了解HIV-1特异性CD 8 + T细胞上KIR和NKG 2A受体表达的作用 功能在本申请中，KIR和NKG 2受体的表达谱将在 HIV-1感染不同阶段受试者中的CD 8 + T细胞，以确定NK细胞受体的动力学 上调，以阐明NK细胞受体表达对CD 8 + T细胞的影响。 功能，这些受体是否优先富集在HIV特异性CD 8 + T细胞表面， 以及这种抑制作用是否可以逆转。此外，解释NK的确切机制 细胞受体介导的CD 8 + T细胞活化的抑制将在免疫学上表征。 突触水平以及TCR信号级联水平。因此，本申请旨在确定是否 在持续性病毒感染期间，导致CD 8 + T细胞活性受损的机制之一可能是 这是由于抑制性NK细胞受体的上调。这些深入的研究旨在了解 KIR/NKG 2A对CD 8 + T细胞的抑制活性的潜在机制肯定会有助于 基础CD 8 + T细胞生物学领域，并可能允许鉴定新的靶点以重建 有效的CD 8 + T细胞免疫在慢性感染的设置，如艾滋病毒。