T cell regulation: CD4+CD25+ FOXP3+ T cells in acute and chronic HIV-1 infection

T 细胞调节：急性和慢性 HIV-1 感染中的 CD4 CD25 FOXP3 T 细胞

• 批准号: 7413442
• 负责人: Marylyn Martina Addo
• 金额: $ 13.01万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413442
• 关键词: Acute; Address; Allografting; Antigens; Autoimmune Diseases; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Communicable Diseases; Equilibrium; Evaluation; Frequencies; Future; HIV; HIV-1; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Individual; Infection; Inflammation; Intervention; Investigation; Ligands; Mediating; Peripheral; Play; Population; Process; Role; Specificity; Staging; T cell regulation; T-Lymphocyte; TLR8 gene; Thinking; Vaccine Research; Viral Antigens; Virus Diseases; base; functional decline; human TLR8 protein; insight; pathogen; response; tumor

DESCRIPTION (provided by applicant): HIV-1 infection is associated with loss of CD4+ T cells, chronic immune activation and progressive immune dysfunction. HIV-specific responses, particularly those of CD4+ T cells, become impaired early after infection and the basis for this decline in function has not been fully elucidated. Regulatory T cells (Tregs), a cellular subset with constitutive immunosuppressive activity first described in the context of autoimmune disorders, are one of several cellular subsets involved in controlling inappropriate or excessive immune activation. CD25+CD4+Foxp3+ Tregs have been demonstrated to suppress antigen-specific T cell responses directed against tumors and allografts as well as against parasitic, bacterial, fungal, and viral antigens. Tregs are thought to play a prominent role in maintaining the delicate balance between an immune response that is sufficiently robust to clear the infection and the immunopathological consequences of sustained immune activation and inflammation. Recent studies in HIV-1 infection indicate that regulatory T cells contribute to HIV-induced immune dysfunction and they were shown to suppress HIV-1 specific CD4+ T cell and CD8+ T cell responses in vitro. However, whether or not the frequency of peripheral Tregs is increased in chronic HIV-infected individuals remains controversial and the exact role of Tregs in HIV-1 infection is poorly understood. Detailed studies in this evolving field of T cell regulation are needed to begin to understand the exact function of Tregs in HIV-1 infection. Methodological barriers to isolate pure Treg populations have recently been overcome. We therefore propose to perform a detailed analysis of the frequency and function of Tregs in different stages of HIV-1 infection with the hypothesis that Tregs are impaired during the chronic stage of HIV-1 infection and thus contribute to enhanced immune activation. We hypothesize that Toll-like receptor 8 mediated effects impair regulatory T cell function and thus contribute to immune activation in chronic HIV-1 infection. The following specific aims will be addressed: 1. Evaluation of regulatory T cell activity in different stages of HIV-1 infection; 2. Assessment of HIV-1-specificity of regulatory T cells in HIV-1 infection and 3. Investigation of the impact of HIV-1-encoded TLR8 ligands on the function of regulatory T cells. These studies will further our understanding of regulation of T cell immunity in HIV-1 infection and will provide important insights for potential future immunotherapeutic interventions and vaccine research.

描述（由申请人提供）：HIV-1感染与CD 4 + T细胞丢失、慢性免疫激活和进行性免疫功能障碍相关。HIV特异性反应，特别是CD 4 + T细胞的反应，在感染后早期受损，这种功能下降的基础尚未完全阐明。调节性T细胞（Tcells）是在自身免疫性疾病的背景下首次描述的具有组成性免疫抑制活性的细胞亚群，是参与控制不适当或过度免疫激活的几种细胞亚群之一。已经证明CD 25 + CD 4 + Foxp 3 + T细胞抑制针对肿瘤和同种异体移植物以及针对寄生虫、细菌、真菌和病毒抗原的抗原特异性T细胞应答。TMF被认为在维持足够稳健以清除感染的免疫应答与持续免疫激活和炎症的免疫病理学后果之间的微妙平衡方面发挥突出作用。HIV-1感染的最新研究表明，调节性T细胞有助于HIV诱导的免疫功能障碍，并且它们在体外显示出抑制HIV-1特异性CD 4 + T细胞和CD 8 + T细胞应答。然而，外周THBG的频率是否在慢性HIV感染者中增加仍然存在争议，THBG在HIV-1感染中的确切作用知之甚少。需要对T细胞调节这一不断发展的领域进行详细研究，以开始了解TcR在HIV-1感染中的确切功能。分离纯Treg群体的方法学障碍最近已被克服。因此，我们建议进行一个详细的分析的频率和功能的Tcirrhosis在不同阶段的HIV-1感染的假设，Tcirrhosis是受损的HIV-1感染的慢性阶段，从而有助于增强免疫激活。我们假设Toll样受体8介导的效应损害调节性T细胞功能，从而有助于慢性HIV-1感染的免疫激活。具体目标如下：1。评价HIV-1感染不同阶段的调节性T细胞活性; 2.评估HIV-1感染中调节性T细胞的HIV-1特异性和3.研究HIV-1编码的TLR 8配体对调节性T细胞功能的影响。这些研究将进一步加深我们对HIV-1感染中T细胞免疫调节的理解，并将为未来潜在的免疫干预和疫苗研究提供重要的见解。