CD8+ T Cell exhaustion during Toxoplasmosis

描述：弓形体脑炎(TE)是晚期HIV感染患者中最常见的威胁生命的中枢神经系统感染之一。尽管CART(联合抗逆转录病毒疗法)导致的TE发病率大幅下降，但在一些感染率较高的国家，它仍然是一个问题。血栓栓塞症仍是艾滋病患者最常见的脑部并发症。人们认为，即使在后ART时代，致命的弓形虫病仍然是艾滋病毒感染者的一个重大问题。过去二十年中进行的研究，包括在我们实验室进行的研究表明，CD8+T细胞在针对疫苗株产生的保护性免疫和在携带慢性弓形虫感染的小鼠的感染控制中都发挥着关键作用。然而，尽管诱导了强大的CD8+T细胞免疫，但敏感的动物株无法阻止潜伏感染的重新激活，它们会发生TE。我们实验室最近的研究表明，来自敏感品系小鼠的CD8+T细胞会耗尽，失去控制慢性感染的功能。CD8+T细胞的衰竭归因于这些细胞上PD-1(一种众所周知的抑制分子)表达的逐步上调。尽管阻断PD-1与其配体PDL-1的相互作用可激活CD8+T细胞反应，但不能挽救高度耗尽的细胞。该提案的初步数据显示，除了PD-1，来自易感动物的CD8+T细胞还表现出其他抑制分子的表达增加，如LAG-3、2B4和CTLA-4。因此，可能需要阻断多种抑制剂来恢复CD8+T细胞的功能。此外，导致CD8+T细胞耗竭的抑制性受体上调的机制还需要评估。该提案有三个具体目标。在特定的目标1中，我们将对感染动物的CD8+T细胞表达多种抑制受体的动力学和模式进行研究。这将提供有关扭转衰竭所需的抗体鸡尾酒的重要信息，从而防止潜伏感染的重新激活。在特定目标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，最适的IL-21水平在维持CD8+T细胞功能反应中起着关键作用。在这个特定的目标中，产生IL-21的CD4+T细胞在CD8+T细胞的长期功能编程中的重要作用将被确定。最后在第三个具体目标中，CD40激动剂治疗的作用 作为抗体的补充治疗，将检测抑制分子的阻断情况。这些研究提供的信息将对制定预防TE的治疗方案大有裨益。如上所述，TE仍然是艾滋病毒感染者的一个严重问题。

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.