CD8+ T Cell exhaustion during Toxoplasmosis

弓形虫病期间 CD8 T 细胞耗竭

• 批准号: 8896135
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 48.52万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896135
• 关键词: Acquired Immunodeficiency Syndrome; Activities of Daily Living; Acute; Agonist; Animals; Antibodies; Apoptosis; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Central Nervous System Infections; Cerebrum; Chronic; Complication; Country; Data; Defect; Development; Down-Regulation; Encephalitis; Exhibits; Functional disorder; Goals; HIV; HIV Infections; Hand; Health; Helper-Inducer T-Lymphocyte; High Prevalence; Immune; Immunity; Incidence; Individual; Infection; Infection Control; Kinetics; Laboratories; Life; Ligands; Measures; Mediating; Memory; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Organism; Patients; Pattern; Play; Population; Process; Publications; Publishing; Regimen; Role; Seroprevalences; Staging; System; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Therapeutic Agents; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Up-Regulation; Vaccines; advanced disease; antiretroviral therapy; base; cytokine; exhaust; exhaustion; inhibitor/antagonist; insight; latent infection; mortality; mouse model; novel; pathogen; prevent; programs; receptor; research study; response

DESCRIPTION: Toxoplasmic encephalitis (TE) is one of the most common life threatening central nervous system infections in HIV infected patients with advanced disease. Although incidence of TE as a result of cART (combination antiretroviral therapy) has decreased substantially, it continues to be a problem in some countries with high prevalence of infection. TE is still the most common cerebral complication in AIDS patients. It is believed that even in post ART era, fatal toxoplasmosis remains a significant problem in HIV infected individuals. Studies conducted during last two decades, including those carried out in our laboratory have demonstrated a critical role for CD8+ T cells, both in protective immunity generated against vaccine strains and control of infection in the mice carrying chronic Toxoplasma infection. However, despite induction of strong CD8+ T cell immunity, susceptible strains of animals are unable to prevent reactivation of latent infection and they develop TE. Recent studies from our laboratory have demonstrated that CD8+ T cells from the susceptible strain of mice become exhausted and lose their functional ability to keep chronic infection under control. CD8+ T cell exhaustion was attributed to graded up-regulation of PD-1 (a well-known inhibitory molecule) expression on these cells. Although blockade of PD-1 interaction with its ligand PDL-1 invigorated CD8+ T cell response, highly exhausted cells could not be rescued. Preliminary data for the proposal demonstrates that in addition to PD-1, CD8+ T cells from susceptible animals exhibited increased expression of other inhibitory molecules like LAG-3, 2B4 and CTLA-4. Thus blockade of multiple inhibitors may be needed to restore CD8+ T cell functionality. Moreover, mechanism responsible for upregulation of inhibitory receptors leading to CD8+ T cell exhaustion needs to be evaluated. The proposal has three specific aims. In specific aim 1, kinetics and pattern of multiple inhibitory receptors expressed by CD8+ T cells from infected animals will be performed. This will provide important information about the antibody cocktail needed for reversing the exhaustion so that reactivation of latent infection is prevented. In specific aim 2, underlying mechanism responsible for CD8+ T cell exhaustion in mice carrying chronic Toxoplasma infection will be evaluated. Preliminary data suggests that optimal IL-21 levels play critical role in maintaining functional CD8+ T cell response. In this specific aim important role of IL-21 producing CD4+ T cells in programming of CD8+ T cells for long-term functionality will be determined. Finally in the third specific aim, role of CD40 agonist treatment as a supplemental therapy to antibody blockade of inhibitory molecules will be assayed. Information generated from these studies will be highly beneficial to develop therapeutic regimen for preventing TE which as stated above continues to be a serious problem for HIV infected population.

描述：弓形虫性脑炎（TE）是艾滋病毒感染晚期疾病患者中中枢神经系统感染的最常见生命之一。尽管CART（组合抗逆转录病毒疗法）的TE发生率显着降低，但在某些国家感染率较高的国家中，这仍然是一个问题。 TE仍然是艾滋病患者中最常见的大脑并发症。人们认为，即使在艺术时代，致命的弓形虫病仍然是艾滋病毒感染者的重大问题。在过去的二十年中进行的研究（包括在我们实验室中进行的研究）证明了CD8+ T细胞的关键作用，这既在针对疫苗菌株产生的保护性免疫和控制感染的保护性免疫中，并控制了携带慢性毒素感染的小鼠。然而，尽管诱导了强烈的CD8+ T细胞免疫，但动物的易感性菌株仍无法防止潜在感染重新激活并发展出TE。我们实验室的最新研究表明，来自小鼠易感性菌株的CD8+ T细胞筋疲力尽，失去了将慢性感染控制的功能能力。 CD8+ T细胞耗尽归因于这些细胞上PD-1（一种众所周知的抑制分子）表达的上调。尽管PD-1与其配体PDL-1的相互作用阻碍了激动人心的CD8+ T细胞反应，但无法挽救高度耗尽的细胞。该提案的初步数据表明，除了PD-1外，易感动物的CD8+ T细胞外，还表现出其他抑制性分子（如LAG-3，2B4和CTLA-4）的表达增加。因此，可能需要封锁多个抑制剂以恢复CD8+ T细胞功能。此外，需要评估导致导致CD8+ T细胞耗尽的抑制受体上调的机制。该提案具有三个具体目标。在特定的目标1中，将执行由感染动物CD8+ T细胞表达的多种抑制受体的动力学和模式。这将提供有关逆转疲劳所需的抗体鸡尾酒的重要信息，以便防止潜在感染的重新激活。在特定的目标2中，将评估携带慢性毒素感染的小鼠CD8+ T细胞耗尽的基本机制。初步数据表明，最佳IL-21水平在维持功能CD8+ T细胞响应中起关键作用。在这一特定目标中，将确定产生CD4+ T细胞在CD8+ T细胞编程中的长期功能的重要作用。最后，在第三个特定目标中，CD40激动剂治疗的作用 作为对抗体阻断抑制性分子的补充疗法。这些研究产生的信息将非常有益于开发治疗方案，以防止TE，如上所述，对于HIV感染人群而言，这仍然是一个严重的问题。