CD4 dysfunction and cerebral toxoplasmosis

摘要 潜伏的弓形虫病仍然是免疫功能低下的感染者的问题 个体和弓形体脑炎(TE)是最常见的威胁生命的疾病之一 这些患者的中枢神经系统感染。潜伏期的重新激活 弓形虫病归因于缺乏足够的CD4T细胞帮助而损害CD8 对寄生虫的T细胞免疫。与人类相似，弓形虫病的小鼠模型 已经证明了CD4T细胞在维持强大的CD8T细胞中的关键作用 细胞免疫。在最近的一项研究中，我们证明CD8T功能障碍会导致 慢性感染宿主的重新激活是CD4T细胞耗尽的结果。 抗原特异性未耗尽的CD4T细胞治疗慢性宿主可恢复 CD8T细胞的功能和防止重新激活。有趣的是，CD4的耗尽与 转录因子blimp-1的上调，从而导致 抑制受体在这些细胞上的表达。建议书的初步数据 提示在隐匿性弓形虫病期间，blimp-1的表达增加会导致 抗原特异的表观遗传学变化，CD4中医(中央记忆)亚集。这个 转录因子获得对该群体上染色质位点的可及性并发生变化 它们的表观遗传景观。BLIMP-1消融重新激活CD4T细胞 抑制性受体下调和正向共刺激蛋白表达增加 分子。该提案有两个具体目标。在目标1中，我们将确定染色质 气球飞艇-1绑定到的可访问的网站。我们计划定义表观遗传学 隐匿性弓形虫感染时CD4、Tcm的变化导致其衰竭。在AIM 2 将进行研究以评估CD4T细胞功能是否因BLIMP-1而恢复 消融依赖于4-1BB和OX40或其他共刺激因子的上调 目标1中确定的分子。我们将确定细胞内的信号是否通过这些共同的- 刺激分子是BLIMP-1最佳恢复CD4T细胞功能所必需的 消融的细胞。最后，将进行研究以确定CD4T细胞是否接受了 共刺激分子激动剂下调CD8细胞表面抑制性受体 并赋予这些细胞强大的效应器细胞毒程序，这对包含 慢性弓形虫感染。

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.