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: 7224589
• 负责人: Galit Alter
• 金额: $ 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224589
• 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; Research Personnel; 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

DESCRIPTION (provided by applicant): 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 HIV specific 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 application 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.

描述（由申请人提供）：病毒特异性CD 8 + T细胞通过直接消除感染细胞和分泌大量可溶性因子在控制病毒感染中发挥核心作用。然而，尽管在慢性HIV-1感染中诱导了强烈和广泛的HIV特异性CD 8 + T细胞应答，但这些细胞逐渐丧失了关键的效应子功能。许多最近的研究表明，CD 8 + T细胞的重要子集似乎在遇到抗原后上调抑制性“NK细胞受体”表达，并且表达NK细胞受体的CD 8 + T细胞在慢性感染的小鼠中持续存在，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，以及人类中的C型凝集素家族（NKG 2）和小鼠中的Ly 49家族。这些受体在CD 8 + T细胞上的表达可以对肿瘤特异性和病毒特异性T细胞的功能能力产生深远的影响。最近，在慢性HIV-1感染中的CD 8 + T细胞离散群体中也描述了KIR和NKG 2A表达水平的增加。鉴于这些受体的深刻抑制作用，本申请旨在更好地了解KIR和NKG 2A受体表达对HIV-1特异性CD 8 + T细胞功能的作用。在本申请中，将在HIV-1感染的不同阶段的受试者的CD 8 + T细胞上表征KIR和NKG 2受体的表达谱，以确定HIV-1感染中NK细胞受体上调的动力学，以阐明NK细胞受体表达对CD 8 + T细胞功能的影响，这些受体是否优先富集在HIV特异性CD 8 + T细胞的表面上，以及这种抑制作用是否可以逆转。此外，解释NK细胞受体介导的CD 8 + T细胞活化抑制的精确机制将在免疫突触水平以及TCR信号级联水平上表征。因此，本申请旨在确定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是否可能是由于抑制性NK细胞受体的上调。这些旨在了解KIR/NKG 2A对CD 8 + T细胞抑制活性的潜在机制的深入研究肯定会有助于基础CD 8 + T细胞生物学领域，并可能允许鉴定新靶点，以在慢性感染（如HIV）的背景下重建有效的CD 8 + T细胞免疫。