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

描述(申请人提供)：流感是发病率和死亡率的主要原因，每年导致数千人死亡和更多的呼吸衰竭。目前的治疗是针对病毒的，因此受到流感快速演变能力的限制 对危重病人常常无效。显然，需要新的治疗策略。流感的呼吸衰竭通常是由于对病毒的免疫反应失调造成的。长时间的病毒复制或持续的炎症导致免疫介导的肺损伤，可导致严重的肺炎，并使宿主容易发生继发性感染。调节宿主免疫反应已被认为是一种新的治疗方法。因此，更好地了解促进病毒清除和预防免疫介导的肺损伤的宿主机制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)是一种表达在包括树突状细胞(DC)和终末分化T细胞在内的天然免疫细胞上的调节蛋白。目前的证据表明，TIM3对先天免疫反应的启动和获得性免疫反应的终止都是重要的。我们认为，TIM3活性的调节可用于增强宿主防御，减轻流感感染时免疫介导的肺损伤。在流感期间，CD103呼吸道树突状细胞(RDC)对病毒抗原的交叉提呈对于产生抗病毒的CD8 T细胞应答至关重要。这些细胞的缺失大大延迟了病毒的清除，并增加了疾病的严重性。我们提供的数据表明，TIM3在CD103 RDC上高度表达，并调节这些细胞的功能。我们假设TIM3通过增强CD103区域树突状细胞的抗原交叉提呈来促进对流感的早期先天反应。在这个应用中，我们将确定TIM3在流感期间CD103 RDC上的作用，并描述TIM3介导其活性的机制。为了便于CD103 RDC上TIM3的研究，我们培育了一种允许细胞特异性删除TIM3的转基因小鼠。具体地说，我们建议(1)确定CD103 RDC上的TIM3在启动CD8T细胞对流感的反应中的作用；(2)确定TIM3调节DC抗原交叉递送的机制；(3)确定TIM3对人肺中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.