Regulation of the host immune response to influenza by the checkpoint receptor Tim3

项目总结 流感仍然是发病率和死亡率的重要原因，目前的治疗方法疗效有限。 流感的呼吸衰竭是由于病毒复制时间延长或由 过度活跃的免疫反应。因此，对监管机制的更好理解 宿主对IAV的免疫反应可能导致新的治疗方法。效应器CD8+T细胞负责 甲型流感病毒(IAV)在初次感染期间的清除，但也与免疫- 介导性肺损伤。效应器CD8+T细胞也能激发流感特异性CD8+组织的驻留记忆 T细胞(Trm)，介导异型免疫，降低随后IAV感染的严重程度。 因此，必须严格控制CD8+T细胞对IAV应答的大小和质量，以实现 清除病毒，限制免疫介导的肺损伤，促进组织驻留记忆的形成。 树突状细胞(DC)激活淋巴结中的原始T细胞，以产生效应性CD8+T细胞反应， 与感染肺内的效应者CD8+T细胞相互作用，促进病毒清除和减弱 免疫病理学，是产生最佳CD8+Trm所必需的。因此，DC在以下方面发挥了关键作用 调节效应CD8+T细胞和保护性记忆的形成。效应器CD8+T细胞 也受抑制性(即检查点)受体的调节。T细胞免疫球蛋白和粘蛋白结构域3(TIM3) 是一种重要的检查点受体，在活化的T细胞上诱导，并在 华盛顿特区。TIM3调节对IAV的免疫反应，但尚不清楚它是否限制病毒清除 或保护肺部免受损伤。我们之前证明了TIM3减弱了效应者CD8+T细胞反应 并在IAV的小鼠模型中预防死亡。我们现在有数据表明，TIM3 促进DC的抗原交叉提呈--这是产生效应器和组织的关键过程 IAV感染中的驻留记忆性CD8+T细胞我们的中心假设是TIM3决定了 平衡病毒清除和肺损伤，促进CD8+Trm的形成。在目标1中，我们 将验证TIM3通过DC和DC介导的激活促进抗原交叉递呈的假设 幼稚CD8+T细胞在IAV感染过程中的变化。具体地说，我们将(A)确定细胞内机制 被TIM3用来促进交叉呈现，(B)表征TIM3在 人肺树突状细胞，以及(C)确定TIM3在IAV期间肺树突状细胞激活原始CD8+T细胞中的作用 感染。在目标2中，我们将检验TIM3促进病毒清除和减弱免疫功能的假设。 介导IAV感染过程中的肺损伤，并促进IAV诱导的CD8+Trm的形成。实验在 这一目标将确定TIM3在IAV期间调节肺内效应CD8+T细胞反应中的作用 (B)确定TIM3在IAV诱导的CD8+Trm形成中的作用。这些实验是 将TIM3开发为流感治疗靶点的关键第一步。

PROJECT SUMMARY Influenza remains an important cause of morbidity and mortality and current therapies have limited efficacy. Respiratory failure in influenza results from either prolonged viral replication or lung injury induced by an over exuberant immune response. It follows that a better understanding of the mechanisms that regulate the host immune response to IAV could lead to new therapies. Effector CD8+ T cells are responsible for clearance of influenza A virus (IAV) during primary infection but have also been implicated in immune- mediated lung injury. Effector CD8+ T cells also give rise to influenza-specific CD8+ tissue resident memory T cells (Trm), which mediate heterosubtypic immunity, decreasing the severity of subsequent IAV infection. Thus, the magnitude and quality of the CD8+ T cell response to IAV must be tightly controlled to achieve viral clearance, limit immune-mediated lung injury and promote the formation of tissue-resident memory. Dendritic cells (DC) activate naïve T cells in the lymph node to generate an effector CD8+ T cell response, interact with effector CD8+ T cells within infected lung to promote viral clearance and attenuate immunopathology and are required for the generation of optimal CD8+ Trm. Thus, DC play a critical role in regulating both effector CD8+ T cells and in the formation of protective memory. Effector CD8+ T cells are also regulated by inhibitory (i.e. checkpoint) receptors. T cell immunoglobulin and mucin domain 3 (Tim3) is an important checkpoint receptor that is induced on activated T cells and constitutively expressed on DC. Tim3 modulates the immune response to IAV, but it is not known whether it constrains viral clearance or protects from lung injury. We previously demonstrated Tim3 attenuates effector CD8+ T cell responses and protects against mortality in a mouse model of IAV. We now have data demonstrating that Tim3 promotes antigen cross presentation by DC – a process critical for generating both effector and tissue resident memory CD8+ T cells in IAV infection. Our central hypothesis is that Tim3 determines the balance between viral clearance and lung injury and promotes the formation of CD8+ Trm. In Aim #1, we will test the hypothesis that Tim3 promotes antigen cross presentation by DC and DC-mediated activation of naive CD8+ T cells during IAV infection. Specifically, we will (A) identify the intracellular mechanisms utilized by Tim3 to promote cross presentation, (B) characterize the expression and function of Tim3 on human lung DC, and (C) determine the role of Tim3 on lung DC in activating naïve CD8+ T cells during IAV infection. In Aim #2, we will test the hypothesis that Tim3 promotes viral clearance and attenuates immune- mediated lung injury during IAV infection and promotes IAV-induced CD8+ Trm formation. Experiments in this aim will A) define the effect of Tim3 in regulating effector CD8+ T cell responses in the lung during IAV infection and (B) determine the role of Tim3 in IAV-induced CD8+ Trm formation. These experiments are a critical first step toward developing Tim3 as a therapeutic target for influenza.