Tim3 is a novel regulator of dendritic cell-T cell interactions in influenza

描述（由申请人提供）：流感是发病和死亡的主要原因，每年导致数千人死亡和更多的呼吸衰竭发作。目前的治疗方法针对病毒，因此受到流感快速演变能力的限制 并且在危重患者中经常无效。显然，需要新的治疗策略。流感中的呼吸衰竭通常是由对病毒的免疫反应失调引起的。长期病毒复制或持续性炎症导致免疫介导的肺损伤可导致严重的肺炎，并使宿主易于继发感染。调节宿主免疫应答已被提出作为一种新的治疗方法。因此，更好地了解宿主机制，促进病毒清除和预防免疫介导的肺损伤可能具有强大的治疗意义。T细胞免疫球蛋白和粘蛋白结构域3（Tim3）是在先天免疫细胞（包括树突状细胞（DC）和终末分化的T细胞）上表达的调节蛋白。目前的证据表明，Tim3对于先天免疫应答的启动和适应性免疫应答的终止都是重要的。我们提出，Tim3活性的调节可用于增强宿主防御和减弱流感感染中免疫介导的肺损伤。CD103+呼吸道DC（rDC）对病毒抗原的交叉呈递对于流感期间产生抗病毒CD8+ T细胞应答至关重要。这些细胞的缺失显著延迟病毒清除并增加疾病严重程度。我们目前的数据显示，Tim3是高度表达的CD103+ rDC，它调节这些细胞的功能。我们推测Tim3通过增强CD103+ rDCs的抗原交叉呈递来促进对流感的早期先天性应答。在本申请中，我们将定义Tim3在流感期间对CD103+ rDCs的作用，并描述Tim3介导其活性的机制。为了促进CD103+ rDC上Tim3的研究，我们已经产生了允许细胞特异性缺失Tim3的遗传修饰的小鼠。具体而言，我们提出（1）确定⑶ 103 + rDCs上的Tim3在启动针对流感的⑶ 8 + T细胞应答中的作用，（2）确定Tim3调节DCs的抗原交叉呈递的机制，以及（3）确定Tim3在人肺中对DC亚群的作用。

DESCRIPTION (provided by applicant): Influenza is a major cause of morbidity and mortality, leading to thousands of deaths and many more episodes of respiratory failure annually. Current therapies target the virus and are therefore limited by the capacity of influenza to rapidly evolve and are frequently ineffective in critically ill patients. Clearly, new therapeutic strategies are needed. Respiratory failure in influenza often results from a dysregulated immune response to the virus. Prolonged viral replication or persistent inflammation resulting in immune-mediated lung injury can lead to severe pneumonitis and predisposes the host to secondary infections. Modulation of the host immune response has been proposed as a novel approach to therapy. Thus, a better understanding of host mechanisms that promote viral clearance and prevent immune-mediated lung injury may have powerful therapeutic implications. T cell immunoglobulin and mucin domain 3 (Tim3) is a regulatory protein expressed on innate immune cells, including dendritic cells (DCs), and terminally differentiated T cells. Current evidence suggests that Tim3 is important for both initiation of the innate immune response and termination of the adaptive immune response. We propose that modulation of Tim3 activity can be used to augment host defense and attenuate immune- mediated lung injury in influenza infection. Cross presentation of viral antigens by CD103+ respiratory DCs (rDCs) is critical for the generation of an anti-viral CD8+ T cell response during influenza. Deletion of these cells significantly delays viral clearance and increases disease severity. We present data showing that Tim3 is highly expressed on CD103+ rDCs and that it regulates the function of these cells. We hypothesize that Tim3 promotes the early innate response to influenza by augmenting antigen cross presentation by CD103+ rDCs. In this application, we will define the role of Tim3 on CD103+ rDCs during influenza and delineate the mechanisms by which Tim3 mediates its activity. To facilitate the study of Tim3 on CD103+ rDCs, we have generated a genetically modified mouse that allows cell-specific deletion of Tim3. Specifically we propose (1) To determine the role of Tim3 on CD103+ rDCs in initiating the CD8+ T cell response to influenza, (2) To determine the mechanism by which Tim3 regulates antigen cross presentation by DCs and (3) To define the role of Tim3 on DC subsets in the human lung.