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

检查点受体 Tim3 调节宿主对流感的免疫反应

基本信息

批准号：
10614585
负责人：
Josalyn L Cho
金额：
$ 55.03万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614585
关键词：
Acute Affect Antigens Attenuated Blocking Antibodies CD8-Positive T-Lymphocytes CD8B1 gene Cell Survival Cells Cessation of life Cross Presentation Data Dendritic Cells Disease Equilibrium Generations Goals Human Immune Immune response Immunity Immunoglobulins Impairment Infection Influenza Influenza A virus Ligands Lung Mediating Memory Morbidity - disease rate Mucins Mus Outcome Pharmaceutical Preparations Phase Play Primary Infection Process Qualifying Regulation Research Respiratory Failure Role Serotyping Severities Signal Pathway Signal Transduction T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Viral Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication cell type checkpoint receptors cross immunity experimental study genetic regulatory protein immune checkpoint immunopathology immunoregulation improved outcome influenza infection lung injury lymph nodes mortality mouse model neutralizing antibody novel novel therapeutics prevent receptor respiratory virus response targeted treatment therapeutic target tissue resident memory T cell tool viral resistance

项目摘要

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.

项目概要流感仍然是发病和死亡的重要原因，目前的治疗方法疗效有限。流感导致的呼吸衰竭是由于病毒复制时间延长或流感病毒引起的肺损伤造成的。过度旺盛的免疫反应。由此可见，更好地理解调节机制宿主对 IAV 的免疫反应可能会带来新的疗法。效应 CD8+ T 细胞负责甲型流感病毒（IAV）在原发感染期间被清除，但也与免疫相关介导的肺损伤。效应 CD8+ T 细胞也会产生流感特异性 CD8+ 组织驻留记忆 T 细胞 (Trm) 介导异亚型免疫，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 反应的程度和质量，以实现病毒清除，限制免疫介导的肺损伤并促进组织驻留记忆的形成。树突状细胞 (DC) 激活淋巴结中的幼稚 T 细胞，产生效应 CD8+ T 细胞反应，与受感染肺内的效应 CD8+ T 细胞相互作用，促进病毒清除和减弱免疫病理学，并且是产生最佳 CD8+ Trm 所必需的。因此，DC 在调节效应 CD8+ T 细胞和保护性记忆的形成。效应 CD8+ T 细胞是也受抑制性（即检查点）受体调节。 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 细胞上诱导并在直流。 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防止肺损伤。我们之前证明 Tim3 会减弱效应 CD8+ T 细胞反应并防止 IAV 小鼠模型死亡。我们现在有数据表明 Tim3 促进 DC 的抗原交叉呈递——这是产生效应器和组织的关键过程 IAV 感染中的常驻记忆 CD8+ T 细胞。我们的中心假设是 Tim3 决定病毒清除和肺损伤之间的平衡，并促进 CD8+ Trm 的形成。在目标#1中，我们将检验 Tim3 通过 DC 和 DC 介导的激活促进抗原交叉呈递的假设 IAV 感染期间初始 CD8+ T 细胞的变化。具体来说，我们将 (A) 确定细胞内机制 Tim3 利用它来促进交叉呈递，(B) 表征 Tim3 在人肺 DC，(C) 确定 Tim3 在肺 DC 上在 IAV 期间激活初始 CD8+ T 细胞中的作用感染。在目标 #2 中，我们将测试 Tim3 促进病毒清除并减弱免疫的假设。介导 IAV 感染期间的肺损伤并促进 IAV 诱导的 CD8+ Trm 形成。实验于该目标将 A) 定义 Tim3 在 IAV 期间调节肺部效应 CD8+ T 细胞反应的作用 (B) 确定 Tim3 在 IAV 诱导的 CD8+ Trm 形成中的作用。这些实验是这是开发 Tim3 作为流感治疗靶点的关键的第一步。