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

描述(申请人提供)：HIV-1感染与CD4+T细胞丧失、慢性免疫激活和进行性免疫功能障碍有关。HIV特异的反应，特别是CD4+T细胞的反应，在感染后早期就会受损，这种功能下降的基础还没有完全阐明。调节性T细胞(Tregs)是在自身免疫疾病的背景下首次描述的具有结构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个细胞亚群之一。CD25+CD4+Foxp3+Tregs已被证明可以抑制针对肿瘤和同种异体移植物的抗原特异性T细胞反应，以及针对寄生虫、细菌、真菌和病毒抗原的T细胞反应。Treg被认为在维持免疫反应与持续免疫激活和炎症的免疫病理后果之间的微妙平衡方面发挥着突出作用。最近对HIV-1感染的研究表明，调节性T细胞参与了HIV诱导的免疫功能障碍，并在体外被证明能抑制HIV-1特异性的CD4+T细胞和CD8+T细胞的反应。然而，在慢性HIV感染者中，外周血Tregs的频率是否增加仍然存在争议，而且Tregs在HIV-1感染中的确切作用还知之甚少。为了开始了解Tregs在HIV-1感染中的确切功能，需要对这一不断演变的T细胞调节领域进行详细的研究。最近，分离纯Treg种群的方法障碍已经被克服。因此，我们建议对HIV-1感染的不同阶段Tregs的频率和功能进行详细的分析，假设Tregs在HIV-1感染的慢性阶段受到损害，从而有助于增强免疫活性。我们假设Toll样受体8介导的效应损害了调节性T细胞的功能，从而有助于慢性HIV-1感染的免疫激活。将涉及以下具体目标：1.评估HIV-1感染不同阶段的调节性T细胞的活性；2.评估HIV-1感染中调节性T细胞的特异性；3.研究HIV-1编码的TLR8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治疗干预和疫苗研究提供重要的见解。

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.