CD4 dysfunction and cerebral toxoplasmosis

CD4功能障碍与脑弓形体病

• 批准号: 10194373
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 54.71万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10194373
• 关键词: Ablation; Acquired Immunodeficiency Syndrome; Agonist; Antigens; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Maintenance; Cell physiology; Cells; Central Nervous System Infections; Cerebral Toxoplasmosis; Chromatin; Chronic; Communicable Diseases; Data; Development; Down-Regulation; Economics; Encephalitis; Epigenetic Process; Exhibits; Failure; Food; Functional disorder; Goals; HIV Infections; Human; Immunity; Immunocompromised Host; Individual; Infection; Laboratories; Life; Link; Maintenance; Malignant Neoplasms; Mediating; Memory; Methylation; Mus; OX40; Parasites; Patients; Play; Population; Publishing; Receptor Gene; Recovery; Reporting; Role; Signal Transduction; Signaling Molecule; Site; T cell response; Therapeutic; Therapeutic Agents; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; United States; Up-Regulation; base; chronic infection; cytotoxic; exhaustion; experimental study; insight; latent infection; mouse model; pathogen; prevent; programs; promoter; reactivation from latency; receptor; response; restoration; toxoplasmic encephalitis; transcription factor

Abstract Latent toxoplasmosis continues to be a problem for immunocompromised infected individuals and toxoplasmic encephalitis (TE) is one of the most common life threatening central nervous system infections in these patients. The reactivation of latent toxoplasmosis is attributed to lack of adequate CD4 T cell help that compromises the CD8 T cell immunity against the parasite. Similar to humans, mouse models of toxoplasmosis have demonstrated the critical role of CD4 T cells for the maintenance of robust CD8 T cell immunity. In a recent study we demonstrated that CD8 T dysfunction leading to reactivation in chronically infected host is a consequence of CD4 T cell exhaustion. Treatment of chronic host with antigen-specific non-exhausted CD4 T cells can restore CD8 T cell functionality and prevent reactivation. Interestingly, CD4 exhaustion is linked to up-regulation of transcription factor BLIMP-1, which causes an increase in the expression of inhibitory receptors on these cells. Preliminary data for the proposal suggests that during latent toxoplasmosis increased BLIMP-1 expression leads to epigenetic changes in antigen-specific, CD4 TCM (central memory) subset. The transcription factor gains accessibility to chromatin sites on this population and changes their epigenetic landscape. BLIMP-1 ablation re-invigorates CD4 T cells due to downregulation of inhibitory receptors and increased expression of positive co-stimulatory molecules. The proposal has two specific aims. In aim 1 we will determine the chromatin accessible sites on CD4 TCM that BLIMP-1 binds to. We plan to define the epigenetic changes in CD4 TCM during latent toxoplasmosis that leads to their exhaustion. In aim 2 studies will be performed to evaluate if restoration of CD4 T cell function due to BLIMP-1 ablation is dependent on the up-regulation of 4-1BB and OX40 or other costimulatory molecules identified in aim 1. We will determine if cell intrinsic signaling by these co- stimulatory molecules is required for optimal recovery of CD4 T cell function in BLIMP-1 ablated cells. Finally, studies will be performed to determine if CD4 T cells treated with agonist for co-stimulatory molecules downregulate inhibitory receptors on CD8 population and confer strong effector cytotoxic program on these cells that is critical for containing chronic toxoplasma infection.

摘要 潜伏性弓形虫病仍然是免疫功能低下的感染者的一个问题。 弓形体脑炎（TE）是最常见的威胁生命的疾病之一， 中枢神经系统感染。潜伏的激活 弓形虫病是由于缺乏足够的CD 4 T细胞的帮助，损害了CD 8 T细胞对寄生虫的免疫力。与人类相似，弓形虫病的小鼠模型 已经证明了CD 4 T细胞对于维持稳健的CD 8 T细胞的关键作用。 细胞免疫在最近的一项研究中，我们证明了CD 8 T细胞功能障碍导致 在慢性感染宿主中的再活化是CD 4 T细胞耗竭的结果。 用抗原特异性非耗竭CD 4 T细胞治疗慢性宿主可以恢复 CD 8 T细胞功能和防止再活化。有趣的是，CD 4耗竭与 转录因子BLIMP-1的上调，这导致了细胞内 这些细胞上抑制性受体的表达。提案的初步数据 提示在潜伏性弓形虫病期间，BLIMP-1表达增加导致 抗原特异性CD 4 TCM（中央记忆）亚群的表观遗传变化。的 转录因子获得对这一群体的染色质位点的可及性， 他们的表观遗传景观。BLIMP-1消融术可使CD 4 T细胞重新活化， 抑制性受体下调和阳性共刺激因子表达增加 分子。该提案有两个具体目标。在aim 1中，我们将确定染色质 BIMP-1结合的CD 4 TCM上的可接近位点。我们计划定义表观遗传 在潜伏性弓形虫病期间CD 4 TCM的变化导致其衰竭。在aim 2中 将进行研究以评估是否由于BLIMP-1而恢复CD 4 T细胞功能 消融依赖于4-1BB和OX 40或其他共刺激因子的上调。 目标1中确定的分子。我们将确定细胞内在信号是否通过这些共同- BLIMP-1中CD 4 T细胞功能的最佳恢复需要刺激分子 消融细胞最后，将进行研究以确定是否用CD 4 T细胞处理。 共刺激分子的激动剂下调CD 8群体上的抑制性受体 并赋予这些细胞强大的效应细胞毒性程序， 慢性弓形虫感染