Regulation of T Cell Activity During Chronic Infections

描述：(摘自申请者的摘要)CD8 T细胞对 控制病毒感染和肿瘤。然而，目前还不清楚为什么CD8 T细胞的反应有时无法清除某些感染或控制 恶性肿瘤。了解这种失效对于合理的设计是很重要的 针对持续性病毒感染的疫苗和治疗方法以及 癌症。我们已经描述了效应器功能阴性的CD8 T细胞 慢性病毒感染，并表明这种免疫沉默是 在CD4T细胞缺乏的情况下更为明显。因为这些T细胞 出现在持续的抗原刺激条件下，很可能 将发现具有相似效应功能阴性表型的CD8T细胞 在其他慢性病毒感染期间。这样的细胞也有可能出现 在由肿瘤生长引起的持续抗原刺激期间 概念得到了《无响应》文档的支持 肿瘤相关抗原特异性CD8 T细胞。我们假设暴露于 CD8T细胞持续高水平的抗原，当CD4T细胞帮助 限制，通过调节特定的CD8导致这些细胞的失活 T细胞信号转导通路。为了具体解决这一问题，我们建议： 1.确定抗原负载在诱导和维持慢性粒细胞白血病中的作用。 CD8T细胞无反应。 2.确定CD4T细胞应答对维持CD8T的贡献 效应器活动。 3.明确沉默CD8的信号转导途径 T细胞。 明确调控CD8 T细胞效应器活性的机制 持续性病毒感染既具有临床重要性，也具有根本性重要性。 了解CD8 T细胞反应在某些情况下变得无反应的原因 条件对疫苗和疫苗的发展具有重要影响 对抗感染和恶性肿瘤的免疫治疗方法。 此外，制定战略以重新激活先前存在的但在功能上 沉默的T细胞可能有助于免疫介导的病毒感染清除 还有肿瘤。

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.