Regulation of T Cell Activity During Chronic Infections

描述：（改编自申请人的摘要）CD8 T细胞对于 控制病毒感染和肿瘤。目前尚不清楚为什么CD8 T细胞反应有时无法清除某些感染或控制 恶性肿瘤。理解这种失效对于合理设计是很重要的 持续性病毒感染的疫苗和治疗方法， 癌的我们已经描述了效应功能阴性的CD8 T细胞， 慢性病毒感染，并已表明这种免疫沉默是 在CD4 T细胞缺乏的情况下更明显。因为这些T细胞 在持续抗原刺激的条件下出现， 将发现具有相似效应子功能阴性表型的CD8 T细胞 其他慢性病毒感染。这样的细胞也可能出现 在由肿瘤生长引起的持续抗原刺激期间， 这一概念得到了无反应的文献的支持， 肿瘤相关抗原特异性CD8 T细胞。我们假设， CD8 T细胞持续高水平的抗原，当CD4 T细胞的帮助是 限制性的，通过调节特异性CD8 T细胞信号转导通路。为具体解决这一问题，我们建议： 1.为了确定抗原负荷在诱导和维持 CD8 T细胞无反应性。 2.为了确定CD4 T细胞应答对维持CD8 T细胞应答的贡献， 效应子活性 3.为了确定沉默的CD8中被破坏的信号转导途径， T细胞。 定义在免疫过程中调节CD8 T细胞效应子活性的机制 持续的病毒感染在临床上和根本上都是重要的。 理解为什么CD8 T细胞反应在某些情况下变得无反应 条件对疫苗的开发具有重要意义， 免疫治疗方法来对抗感染和恶性肿瘤。 此外，制定战略，重新激活先前存在的，但功能 沉默的T细胞可促进免疫介导的病毒感染清除 和肿瘤。

DESCRIPTION: (Adapted from applicant's abstract) CD8 T-cells are important for controlling viral infections and tumors. It remains unclear, however, why CD8 T-cell responses are sometimes unable to clear certain infections or control malignancies. Understanding this failure is important for the rational design of vaccines and therapeutic treatments for persistent viral infections and cancers. We have described effector-function-negative CD8 T-cells during chronic viral infections and have shown that this immunological silencing is more pronounced under conditions of CD4 T-cell deficiency. Since these T-cells arise under conditions of persistent antigenic stimulation it is likely that CD8 T-cells with similar effector-function-negative phenotypes will be found during other chronic viral infections. Such cells are also likely to emerge during persistent antigenic stimulation resulting from tumor outgrowth and this notion is supported by the documentation of unresponsive tumor-associated-antigen specific CD8 T-cells. We hypothesize that exposure of CD8 T cells to persistently high levels of antigen, when CD4 T cell help is limiting, causes the inactivation of the these cells by modulating specific CD8 T cell signal transduction pathways. To specifically address this we propose: 1. To determine the role of antigen load on the induction and maintenance of CD8 T cell unresponsiveness. 2. To determine the contribution of CD4 T cell responses to sustaining CD8 T effector activity. 3. To define the signal transduction pathway that is disrupted in silenced CD8 T cells. Defining the mechanisms which regulate CD8 T cell effector activity during persistent viral infections is of both clinical and fundamental importance. Understanding why CD8 T cell responses become unresponsive under certain conditions has important implications for the development of vaccines and immunotherapeutic approaches to combat infections and malignancies. Furthermore, devising strategies to reactivate preexisting but functionally silenced T cells may facilitate immune mediated clearance of viral infections and tumors.