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：弓形虫脑炎 (TE) 是 HIV 感染晚期患者最常见的危及生命的中枢神经系统感染之一。尽管 cART（联合抗逆转录病毒治疗）导致 TE 的发病率大幅下降，但在一些感染率较高的国家，这仍然是一个问题。 TE 仍然是艾滋病患者最常见的脑部并发症。据信，即使在后 ART 时代，致命的弓形体病仍然是 HIV 感染者的一个重大问题。过去二十年进行的研究，包括在我们实验室进行的研究，已经证明 CD8+ T 细胞在针对疫苗株产生的保护性免疫和控制携带慢性弓形虫感染的小鼠的感染方面发挥着关键作用。然而，尽管诱导了强大的 CD8+ T 细胞免疫，但易感动物品系无法阻止潜伏感染的重新激活，从而导致 TE。我们实验室最近的研究表明，来自易感品系小鼠的 CD8+ T 细胞会变得疲惫不堪，并失去控制慢性感染的功能。 CD8+ T 细胞耗竭归因于这些细胞上 PD-1（一种众所周知的抑制分子）表达的分级上调。尽管阻断 PD-1 与其配体 PDL-1 的相互作用可以增强 CD8+ T 细胞的反应，但高度疲惫的细胞无法获救。该提案的初步数据表明，除了 PD-1 之外，来自易感动物的 CD8+ T 细胞还表现出 LAG-3、2B4 和 CTLA-4 等其他抑制分子的表达增加。因此，可能需要阻断多种抑制剂来恢复 CD8+ T 细胞功能。此外，需要评估抑制性受体上调导致 CD8+ T 细胞耗竭的机制。该提案有三个具体目标。在具体目标 1 中，将研究受感染动物的 CD8+ T 细胞表达的多种抑制性受体的动力学和模式。这将提供有关逆转衰竭所需的抗体混合物的重要信息，从而防止潜伏感染的重新激活。在具体目标 2 中，将评估携带慢性弓形虫感染的小鼠 CD8+ T 细胞耗竭的潜在机制。初步数据表明，最佳 IL-21 水平在维持功能性 CD8+ T 细胞反应中发挥着关键作用。在这个具体目标中，将确定产生 IL-21 的 CD4+ T 细胞在 CD8+ T 细胞编程以获得长期功能中的重要作用。最后第三个具体目标，CD40激动剂治疗的作用 作为抗体阻断抑制分子的补充疗法将被测定。这些研究产生的信息将非常有利于开发预防 TE 的治疗方案，如上所述，TE 仍然是 HIV 感染人群的一个严重问题。