NK cell regulation of adaptive immunity during persisting virus infection

描述（由申请人提供）：慢性病毒感染引起的疾病是一个重大的全球性健康问题。CD8+ T细胞不能消除感染，如HIV和HCV，这些感染建立了具有病理后果的持久性。由于几种抑制机制，对这些病毒特异性的T细胞变得无效。尽管T细胞在控制这些病毒感染中具有明显的重要性，但最近的数据表明，自然杀伤（NK）细胞也有助于病毒控制或发病机制。调节NK细胞受体的基因内的遗传多态性与HCV消退相关。我们使用了一个建立的小鼠T细胞耗竭模型，该模型准确地反映了人类T细胞在持续感染后如何进行功能失活。我们发现了一种导致T细胞耗竭的新机制。NK细胞抑制了给予淋巴细胞性脉络丛脑膜炎病毒（LCMV）菌株的小鼠中的病毒特异性CD8+ T细胞反应，该病毒广泛传播并建立持久性。消除感染小鼠中的NK细胞可以改善病毒特异性T细胞的功能和数量，并大大加快病毒清除。我们希望更好地了解NK细胞如何在持续病毒感染的背景下抑制T细胞反应，并了解NK细胞更广泛的免疫调节功能。我们的初步数据显示，来自NK细胞耗尽小鼠的抗原呈递细胞（APC）比来自NK细胞充满小鼠的APC更上级。我们的中心假设是，在传播性病毒感染期间，干扰素水平升高激活NK细胞以抑制或耗尽APC，这导致T细胞耗竭和有限的病毒控制。Aim1的目的是确定暴露于急性或持续LCMV感染的小鼠中NK细胞对T细胞应答的抑制是否受干扰素信号传导的控制。将野生型NK细胞的体内活性与干扰素受体缺陷的那些进行比较。Aim2的目的是检查NK细胞是否消除APC或表达损害T细胞或APC的刺激功能的抑制性细胞因子。Aim3的目的是确定NK细胞是否抑制记忆T细胞和B细胞应答。Aim4的目的是探索记忆NK细胞是否持续影响长期免疫应答。总的来说，这个项目涉及持续性病毒感染的基本免疫生物学。这些努力将支持一项长期的奋进，以探索感染的先天感知和T细胞命运决定之间的联系。这些目标与改进疫苗和治疗剂的设计有关，以防止T细胞耗竭并维持保护性免疫应答，这是NIH，NIAID的既定使命。从该项目中收集的信息可能会超越感染免疫学转化为肿瘤免疫学，其中T细胞耗竭是成功的T细胞免疫疗法的重要障碍。

DESCRIPTION (provided by applicant): Diseases caused by chronic virus infections are a significant worldwide health problem. CD8+ T cells fail to eliminate infections, such as HIV and HCV, which establish persistence with pathological consequences. T cells specific for these viruses are rendered ineffectual due to several suppression mechanisms. Despite the clear importance of T cells in the control of these virus infections, recent data indicate that natural killer (NK) cells also contribute to virus control or pathogenesis. Genetic polymorphisms within genes that regulate NK cell receptors are associated with HCV resolution. We use an established mouse model of T cell exhaustion that accurately reflects how human T cells undergo functional inactivation following persisting infection. We found a new mechanism that contributes to T cell exhaustion. NK cells subdue virus-specific CD8+ T cell responses in mice that are given a strain of lymphocytic choriomeningitis virus (LCMV) that disseminates widely and establishes persistence. Eliminating NK cells in infected mice improves virus-specific T cell function and number and vastly expedites viral clearance. We wish to better understand how NK cells restrain T cell responses in the context of persisting virus infection and understand the wider immunoregulatory functions of NK cells. Our preliminary data show that antigen presenting cells (APC) from NK-depleted mice are superior to APCs from NK cell-replete mice. Our central hypothesis is that during disseminating virus infection, elevated levels of interferon activate NK cells to inhibit or deplete APCs, which leads to T cell exhaustion and limited virus control. The objectives of Aim1 are to determine whether NK cell inhibition of T cell responses is governed by interferon signaling in mice that are exposed to acute or persisting LCMV infection. The in vivo activity of wildtype NK cells will be compared to those that are deficient in interfero-receptors. The objectives of Aim2 are to examine whether NK cells eliminate APCs or express suppressive cytokines that impair T cells or the stimulatory functions of APCs. The objectives of Aim3 are to determine whether NK cells inhibit memory T cell and B cell responses. The objectives of Aim4 are to explore whether memory NK cells persist to influence long-term immune responses. Overall, this project concerns the basic immunobiology of persisting virus infections. These efforts will support a long-term endeavor to explore the links between innate sensing of infection and T cell fate determination. These goals are relevant to improving the design of vaccines and therapeutics to prevent T cell exhaustion and sustain protective immune respones, which is a stated mission of the NIH, NIAID. Information gleaned from this project may translate beyond infection immunology to tumor immunology, where T cell exhaustion is a significant hurdle to successful T cell immunotherapies.