miR146a and CD4 dysfunction during chronic toxoplasmosis

弓形虫是一种顶端复合体寄生虫，是一种致病原虫，可感染 中枢神经系统。孕期感染可导致先天性感染 会有严重的神经后果。在免疫功能受损的个体中重新激活 潜伏的神经病变会导致脑炎。虽然CD8+T细胞发挥着 在控制慢性感染方面发挥重要作用，其维持是 依赖于CD4T细胞提供的关键帮助。在最近的一项研究中，我们 证明CD8 T功能障碍导致慢性感染宿主的重新激活 是CD4T细胞耗尽的结果。用抗原治疗慢性宿主- 特定的未耗尽的CD8T细胞可以恢复CD8T细胞的功能并防止 重新激活。有趣的是，CD4的耗竭与转录因子的上调有关 软式飞艇-1。在本提案中，CD4T细胞功能障碍/衰竭的机制 在慢性弓形虫病期间将接受讯问。建议书的初步数据 提示转录因子BLIMP-1在CD4T细胞上的表达增加是由于 MiR146a的上调，这可能是他们功能障碍的主要原因。这个 提案有两个具体目标。在目标1中，负责增加 将评估CD4T细胞上BLIMP-1的表达。作为初步数据点， MiR146a的作用，将进行研究以确定在缺乏 MiR146a、BLIMP-1表达下调与CD4T细胞耗竭 被阻止了。将进行实验以确定miR146a在 未耗尽的CD4T细胞可能会导致其功能障碍。初步数据显示， 建议显示来自miR146-/-小鼠的抗原特异性CD4T细胞表达 与野生型动物的细胞相比，TRAF6增加。在目标2中，研究 与TRAF6在BLIMP-1调控中起重要作用的新概念有关 对CD4T细胞进行检测。我们计划确定BLIMP-1的表达是否增加 在CD4T细胞上(由于miR146a靶向TRAF6)改变其代谢途径。

Toxoplasmic gondii, an apicomplexan parasite is a pathogenic protozoan that can infect the central nervous system. Infection during pregnancy can result in congenital infection with severe neurological consequences. In immunocompromised individuals reactivation of latent neurological foci can result in encephalitis. Although CD8+ T cells play an important effector role in controlling the chronic infection, their maintenance is dependent on critical help provided by CD4 T cells. In a very 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. In this proposal mechanism responsible for CD4 T cell dysfunction/exhaustion during chronic toxoplasmosis will be interrogated. Preliminary data for the proposal suggests that increased expression of transcription factor BLIMP-1 on CD4 T cells is due to up-regulation of miR146a, which likely is a primary cause of their dysfunction. The proposal has two specific aims. In aim 1 the mechanism responsible for increased BLIMP-1 expression on CD4 T cells will be evaluated. As preliminary data points at the role of miR146a, the studies will be performed to determine if in the absence of miR146a, BLIMP-1 expression can be down-regulated and CD4 T cell exhaustion prevented. Experiments will be performed to determine if over-expression of miR146a on non-exhausted CD4 T cells can lead to their dysfunctionality. Preliminary data for the proposal shows that antigen-specific CD4 T cells from miR146-/- mice express increased TRAF6 as compared to the cells from wild type animals. In aim 2, studies related to novel concept that TRAF6 plays an important role in the regulation of BLIMP-1 on CD4 T cells will be performed. We plan to determine if increased BLIMP-1 expression on CD4 T cells (due to targeting of TRAF6 by miR146a) alters their metabolic pathway.