Regulation of Pathogen-specific T Cell Immunity by Adenosine Generation

描述（由申请人提供）：传染病，包括病毒引起的呼吸道感染和由此引起的急性肺损伤，对受感染的个人、对有效治疗方式的发展和对整个公共卫生倡议构成了相当大的挑战，有效控制病毒感染将需要更详细地了解根除相关病原体所涉及的免疫机制。大多数抗病毒和许多抗菌免疫反应的一个重要组成部分是病原体特异性CD8+T细胞免疫的产生。在解决急性疾病或成功接种疫苗方案后，特异性CD8+效应T细胞（CD8+TE）受到逐渐分化过程的影响，最终建立特异性CD8+T细胞记忆。在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，因为它们能够抑制病毒传播，最大限度地减少临床疾病并避免受感染宿主的潜在死亡。在努力定义高度保护性CD8+TM的分子、表型和功能特性的过程中，我们意外地发现，强大的继发性CD8+T细胞反应的发展取决于有效的腺苷生成和“CD8+TM固有”方式的信号传导。腺苷生成/信号传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概念，挑战了关于腺苷主要作为“免疫抑制”剂的普遍共识，并提出了促进抗病毒T细胞免疫的新治疗途径的可能性。在这里，我们制定了一项研究计划，将识别、询问和表征促进病毒特异性CD8+TM二次反应性的腺苷生成/信号通路中的分子成分，这将定义“促炎”腺苷生成和信号传导的精确病理生理背景（specific Aims 1和2）。这将利用在这些研究过程中获得的相关见解，开发新的治疗方法，旨在增强流感病毒诱导的急性肺损伤模型中的保护性CD8+T细胞免疫（特异性目标3）。病毒引起的急性肺损伤的持续和相当大的负担，特别是在儿童和老年人群中，强调迫切需要新的治疗方法。我们相信，在目前的申请中提出的机制，背景和临床前研究的结合有可能为这种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.