Regulation of Polyoma Virus-Specific CD8+ T Cells

描述(由申请人提供)：致癌DNA病毒建立持续感染和CD8+T淋巴细胞的持续免疫监视通常是消除感染和新转化细胞的关键。抗病毒CD8+T细胞的效应器活性必须紧密平衡，以控制持续感染，而不会因过度破坏感染细胞而导致病理。对多瘤病毒的抗性是由抗病毒CD8+T细胞介导的。多瘤病毒是一种高度致癌的持久性小鼠病原体。易患多发性肿瘤的小鼠在急性感染期间会大量扩增多瘤特异性CD8+T细胞，但这些T细胞缺乏抗原特异性的细胞毒作用。抑制性NK细胞受体CD94/NKG2A是由多瘤特异性CD8+T细胞表达的，负责猝灭其抗原特异性的细胞毒作用。在多瘤耐药小鼠中，表达CD94/NKG2A受体的抗多瘤CD8+T细胞的比例随着感染病毒的清除而增加。我们的总体假设是，在易感小鼠急性感染早期，同源病毒抗原对TCR的过度刺激和/或特定细胞因子的过度产生过早地诱导CD94/NKG2A表达，并抑制抗多瘤CD8+T细胞的效应活性；这导致持续感染的细胞数量增加，并增强病毒致癌的易感性。在本申请中提出的研究寻求(1)确定体内调节和维持抗多瘤CD8+T细胞CD94/NKG2A表达的因素，以及(2)探讨在持续病毒感染的背景下，这种抑制性受体在调节多瘤特异性记忆的CD8+T细胞动态平衡中的潜在作用。多发性肿瘤特异性CD8+T细胞将使用MHC I类四聚体进行物理可视化，并通过细胞内细胞因子的产生、细胞因子的分泌和细胞毒性(体外和体内)的检测来实现功能的可视化。明确体内诱导和维持抗病毒CD8+T细胞上抑制性NK细胞受体表达的机制可能被证明是设计策略以操纵失调的抗病毒免疫反应和控制持续病毒感染的关键。

DESCRIPTION (provided by applicant): Oncogenic DNA viruses establish persistent infection and continuous immunosurveillance by CD8+ T lymphocytes is often essential for eliminating infected and newly transformed cells. The effector activity of antiviral CD8+ T cells must be tightly balanced to control persistent infection without causing pathology resulting from excessive destruction of infected cells. Resistance to polyoma virus, a highly oncogenic persistent mouse pathogen, is mediated by antiviral CD8+ T cells. Mice susceptible to polyoma-induced tumors mount a substantial expansion of polyoma-specific CD8+ T cells during acute infection, but these T cells lack antigen-specific cytotoxicity. An inhibitory NK cell receptor, CD94/NKG2A, is expressed by polyoma-specific CD8+ T cells and is responsible for quenching their antigen-specific cytotoxicity. The proportion of anti-polyoma CD8+ T cells expressing CD94/NKG2A receptors increases in concert with clearance of infectious virus in polyoma tumor-resistant mice. Our overall hypothesis is that excessive TCR stimulation by cognate viral antigens and/or overproduction of specific cytokines early in acute infection in susceptible mice prematurely induces CD94/NKG2A expression on, and inhibits effector activity by, anti-polyoma CD8+ T cells; this leads to elevated numbers of persistently infected cells and an enhanced predisposition to viral oncogenesis. Studies proposed in this application seek (1) to define in vivo factors that regulate and maintain CD94/NKG2A expression by anti-polyoma CD8+ T cells, and (2) to investigate the potential role for this inhibitory receptor in regulating polyoma-specific memory' CD8+ T cell homeostasis in the setting of persistent viral infection. Polyoma-specific CD8+ T cells will be visualized physically using MHC class I tetramers and functionally by intracellular cytokine production, cytokine secretion, and cytotoxicity (both ex vivo and in vivo) assays. Defining in vivo mechanisms that induce and maintain expression of inhibitory NK cell receptors on antiviral CD8+ T cells may prove key to devising strategies to manipulate dysregulated antiviral immune responses and control persistent viral infections.