Regulation of Pathogen-specific T Cell Immunity by Adenosine Generation

描述(申请人提供)：传染病，包括病毒引起的呼吸道感染和由此造成的急性肺损伤，对患病个人、有效治疗方式的发展和整个公共卫生倡议构成了相当大的挑战，有效控制病毒感染需要对根除相关病原体所涉及的免疫机制有更详细的了解。大多数抗病毒和许多抗细菌免疫反应的一个重要组成部分是产生病原体特异性CD8+T细胞免疫。随着急性疾病的解决或疫苗接种方案的成功，特定的CD8+效应T细胞(CD8+TE)经历了一个逐渐分化的过程，最终建立了特定的CD8+T细胞记忆。当再次感染相同或相关的病毒病原体时，病毒特异性CD8+记忆T细胞(CD8+TM)与中和抗体一起提供增强的保护，因为它们能够遏制病毒传播，最大限度地减少临床疾病，并避免受感染宿主的潜在死亡。为了确定高度保护性的CD8+TM的分子、表型和功能特性，我们有了一个意想不到的发现，即强大的二级CD8+T细胞反应的发展依赖于有效的腺苷生成和“CD8+TM-内在”方式的信号传递。腺苷的产生/信号转导可以增强病毒特异性CD8+T细胞反应的概念构成了一个新的概念，挑战了普遍认为腺苷是一种主要的“免疫抑制”剂的共识，并暗示了促进抗病毒T细胞免疫的新的治疗途径的可能性。在这里，我们制定了一个研究计划，该计划将识别、询问和表征腺苷生成/信号通路中促进病毒特异性CD8+TM二级反应的分子成分，将确定“促炎症”腺苷生成和信号传递的精确病理生理背景(特定目标1和2)，并将利用在这些研究过程中获得的相关见解来开发新的治疗方法，旨在在流感病毒诱导的急性肺损伤模型中放大保护性CD8+T细胞免疫(特定目标3)。病毒引起的急性肺损伤，特别是在儿科和老年人群中，继续造成相当大的负担，这突出表明迫切需要新的治疗方法。我们相信，本申请中提出的机械性、关联性和临床前研究的结合，有可能为此类治疗策略的发展提供合理的基础。

DESCRIPTION (provided by applicant): Infectious diseases, including virus-induced respiratory infections and resultant acute lung injury, pose a considerable challenge to afflicted individuals, to the development of effective treatment modalities and to public health initiatives at large and the effective control of viral infections will require a more detailed understanding o the immune mechanisms involved in the eradication of relevant pathogens. An essential component of most antiviral and many antibacterial immune responses is the generation of pathogen-specific CD8+T cell immunity. Following resolution of acute disease or successful vaccination regimens, specific CD8+ effector T cells (CD8+TE) are subject to a gradual differentiation process that culminates in the establishment of specific CD8+T cell memory. Upon re-infection with the same or related viral pathogens, virus-specific CD8+ memory T cels (CD8+TM), together with neutralizing antibodies, provide enhanced protection due to their capacity to curtail viral spread, minimize clinical disease and avert potential death of infected hosts. In an effort to define the molecular, phenotypic and functional properties of highly protective CD8+TM, we have made the unexpected discovery that the development of robust secondary CD8+T cell responses is contingent upon effective adenosine generation and signaling in a "CD8+TM-intrinsic" fashion. The notion that adenosine generation/signaling can potentiate virus-specific CD8+T cell responses constitutes a novel concept, challenges the prevailing consensus about adenosine as a primarily "immunosuppressive" agent, and suggests the possibility of novel therapeutic avenues for promotion of antiviral T cell immunity. Here, we have developed a research plan that will identify, interrogate and characterize the molecular components in the adenosine generation/signaling pathway that promote secondary reactivity of virus- specific CD8+TM, that will define the precise patho-physiological context for "proinflammatory" adenosine generation and signaling (Specific Aims 1 and 2), and that will harness relevant insights obtained in the process of these studies for the development of novel therapeutic approaches that aim to amplify protective CD8+T cell immunity in a model for influenza virus-induced acute lung injury (Specific Aim 3). The continued and considerable burden of virus-induced acute lung injury, especially among pediatric and geriatric populations, emphasizes the urgent need for novel treatment approaches. We believe that the combination of mechanistic, contextual and pre-clinical studies as proposed in the present application has the potential to provide a rational foundation for the development of such therapeutic strategies.