Tregs Differentially Suppress HIV-specific CD8+ T Cells

Tregs 差异性抑制 HIV 特异性 CD8 T 细胞

基本信息

批准号：
8012301
负责人：
HELEN HORTON
金额：
$ 29.48万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8012301
关键词：
Acquired Immunodeficiency Syndrome Alleles Autoimmune Diseases Autoimmunity Biological Assay CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Cellular Immunity Chronic Cleaved cell Cyclic AMP Cytokine Gene Data Disease Disease Progression Effector Cell Enzymes Epitope Mapping Functional disorder Gap Junctions Gene Expression Goals HIV HIV Infections HIV-1 HLA-B27 Antigen HLA-B57 Human Immune response Individual Infection Infection Control Influenza Leukapheresis Light Malignant Neoplasms Mediating Mediator of activation protein Outcome PDE 3B Pathway interactions Phosphatidylinositols Phosphotransferases Proliferating Protein Kinase Regulatory T-Lymphocyte Resistance Role Sampling Serine T cell response T-Lymphocyte Therapeutic Intervention Threonine Virus Virus Diseases Work base cytokine granzyme B killings mouse model peripheral tolerance public health relevance receptor uptake

项目摘要

DESCRIPTION (provided by applicant): CD8+ T cells are key players in the immune response to intracellular infections such as HIV. However, during chronic infection HIV-specific CD8+ T cells become tolerant in that they do not proliferate or kill infected targets as efficiently as virus-specific T cells from other non-persistent viral infections (e.g. influenza). We have shown that HIV-specific T cells restricted by HLA alleles associated with non-progression (HLA-B27/-B57) are resistant to this type of peripheral tolerance, which may explain why rare HIV-infected individuals are protected from progression to AIDS. The mechanism(s) leading to HIV-specific CD8+ T cell tolerance are not known but understanding them is vital to making therapeutic intervention possible. Regulatory T cells (Tregs) are one of the best-described mediators of peripheral tolerance. Our preliminary data show that HIV-specific T cells restricted by HLA-B27/-B57 are resistant to Treg-mediated suppression of proliferative capacity whereas HIV-specific T cells restricted by other HLA alleles are susceptible to Treg-mediated suppression. In this proposal we aim to decipher how Tregs are causing differential suppression of HIV-specific T cells. In Aim 1, we will determine if HIV-specific CD8+ T cells that are resistant to Treg suppression are a common phenomenon in individuals who can control HIV-1. In Aim 2, we will determine which mechanism(s) are utilized by Tregs to suppress HIV-specific T cell responses during chronic infection and how T cells restricted by HLA-B27/B57 are able to escape from this suppression. This study could define why certain HLA alleles are associated with non- progression in HIV-infected individuals. In addition, if we define how specific T cells escape from Treg- mediated suppression this work could have far-reaching implications for therapeutic intervention in other chronic viral infections, cancer and autoimmune disease. PUBLIC HEALTH RELEVANCE: This proposal aims to determine (1) whether HIV-specific T cells that escape Treg-mediated suppression are a common phenomenon in individuals who control HIV-1 infection; (2) the mechanisms utilized by Tregs to suppress HIV-specific T cell function; and (3) how HIV-specific HLA-B27/57-restricted T cells are able to escape Treg-mediated suppression.

描述（由申请人提供）：CD8+ T 细胞是对细胞内感染（例如 HIV）的免疫反应的关键参与者。然而，在慢性感染期间，HIV 特异性 CD8+ T 细胞变得耐受，因为它们不会像其他非持续性病毒感染（例如流感）中的病毒特异性 T 细胞那样有效地增殖或杀死感染目标。我们已经证明，受与非进展相关的 HLA 等位基因 (HLA-B27/-B57) 限制的 HIV 特异性 T 细胞对这种类型的外周耐受具有抵抗力，这可能解释了为什么罕见的 HIV 感染者能够免受进展为 AIDS 的影响。导致 HIV 特异性 CD8+ T 细胞耐受的机制尚不清楚，但了解它们对于使治疗干预成为可能至关重要。调节性 T 细胞 (Treg) 是最被描述的外周耐受介质之一。我们的初步数据表明，受 HLA-B27/-B57 限制的 HIV 特异性 T 细胞对 Treg 介导的增殖能力抑制具有抵抗力，而受其他 HLA 等位基因限制的 HIV 特异性 T 细胞则容易受到 Treg 介导的抑制。在本提案中，我们的目标是破译 Tregs 如何导致 HIV 特异性 T 细胞的差异性抑制。在目标 1 中，我们将确定对 Treg 抑制具有抵抗力的 HIV 特异性 CD8+ T 细胞是否是能够控制 HIV-1 的个体中的常见现象。在目标 2 中，我们将确定 Tregs 在慢性感染期间利用哪些机制来抑制 HIV 特异性 T 细胞反应，以及受 HLA-B27/B57 限制的 T 细胞如何能够逃脱这种抑制。这项研究可以解释为什么某些 HLA 等位基因与 HIV 感染者的非进展相关。此外，如果我们确定特定 T 细胞如何逃离 Treg 介导的抑制，这项工作可能会对其他慢性病毒感染、癌症和自身免疫性疾病的治疗干预产生深远的影响。公共健康相关性：本提案旨在确定 (1) 逃避 Treg 介导抑制的 HIV 特异性 T 细胞是否是控制 HIV-1 感染的个体中的常见现象； (2) Tregs 利用机制抑制 HIV 特异性 T 细胞功能； (3) HIV 特异性 HLA-B27/57 限制性 T 细胞如何能够逃脱 Treg 介导的抑制。