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：
8077329
负责人：
HELEN HORTON
金额：
$ 24.32万
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/8077329
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-Serine-Threonine Kinases Regulatory T-Lymphocyte Resistance Role Sampling T cell response T-Lymphocyte Therapeutic Intervention 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）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细胞变得耐受性，因为它们不会像其他非持久性病毒感染（例如流感）那样有效或杀死感染靶标的病毒特异性T细胞。我们已经表明，受HLA等位基因限制的HIV特异性T细胞（HLA-B27/-B57）对这种类型的外围耐受性具有抵抗力，这可以解释为什么罕见的HIV感染者受到保护不受对AIDS的进展。导致HIV特异性CD8+ T细胞耐受性的机制尚不清楚，但了解它们对于使治疗干预成为可能。调节性T细胞（Tregs）是外围耐受性最好的介体之一。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介导的增殖能力的抑制具有抗性，而受其他HLA等位基因限制的HIV特异性T细胞易于Treg介导的抑制。在此提案中，我们旨在破译Treg如何引起对HIV特异性T细胞的差异抑制。在AIM 1中，我们将确定抗Treg抑制具有抗性的HIV特异性CD8+ T细胞是可以控制HIV-1的个体中的常见现象。在AIM 2中，我们将确定TREG利用哪种机制来抑制慢性感染期间HIV特异性T细胞反应，以及如何限制HLA-B27/B57的T细胞能够从这种抑制中逃脱。这项研究可以定义为什么某些HLA等位基因与HIV感染者的非进展有关。此外，如果我们定义了特定的T细胞如何从Treg介导的抑制中逃脱，则该工作可能对其他慢性病毒感染，癌症和自身免疫性疾病的治疗干预具有深远的影响。公共卫生相关性：该提案旨在确定（1）在控制HIV-1感染的个体中，逃脱Treg介导的抑制的HIV特异性T细胞是否是一种常见现象；（2）Tregs使用的机制抑制HIV特异性T细胞功能；（3）HIV特异性HLA-B27/57限制的T细胞如何能够逃脱Treg介导的抑制。