The Function of MHC Class II on Lung Type II Alveolar Cells

MHC II类对肺II型肺泡细胞的功能

基本信息

批准号：
10383127
负责人：
Sushila Toulmin
金额：
$ 0.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-04-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383127
关键词：
AGTR2 gene Ablation Antigen Presentation Antiviral Agents Autoimmune Diseases Biological Response Modifiers Body Weight decreased CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cause of Death Cells Cessation of life Clinical Communication Complement Cytolysis Data Development Disease Distal Doctor of Philosophy Educational process of instructing Environment Epithelial Cells Equilibrium Exhibits Flow Cytometry Fostering Goals Histocompatibility Antigens Class II Homeostasis Immune Immune response Immunotherapy Impairment In Vitro Infection Infiltration Inflammation Inflammatory Influenza Institution Knowledge Laboratories Leadership Ligands Lower Respiratory Tract Infection Lung Lung diseases MHC Class II Genes Measures Mediating Mediator of activation protein Medical Mentors Methods Molecular Chaperones Morbidity - disease rate Mus Pathologic Patient Care Pennsylvania Peptide/MHC Complex Peptides Phenotype Physicians Physiological Play Process Protein Isoforms Proteins Pulmonary Pathology Pulmonary Surfactants Recording of previous events Recovery Research Resources Role Scientist Signal Transduction Source Stains Structure of parenchyma of lung Surface T cell response T-Cell Depletion T-Lymphocyte Techniques Time Training Training Programs Transfection Tumor-infiltrating immune cells Universities Vaccine Design Vaccines Viral Virus Virus Diseases Work adaptive immune response alveolar type II cell cell type collaborative environment cytokine experimental study extracellular immunopathology improved in vivo influenza infection insight invariant chain lung injury mortality novel pathogen phenotypic biomarker prevent pulmonary function receptor response skills stem cells success trafficking vaccine development

项目摘要

Project Summary: Lower respiratory tract infections are a leading cause of death worldwide. Current vaccines and targeted treatments for such infections, including lung viral infections in particular, are sparse and poorly efficacious. Thus, there is a critical need to improve our understanding of antiviral immune responses in the lung. Morbidity from lung viral infections results from both virus-induced and immune-mediated lung damage, and adaptive immune cells influence both of these processes; they are required for viral clearance, but they are also a main cause of lung immunopathology. The mechanisms that regulate the balance between these protective and pathologic responses are poorly understood. The purpose of this proposal is to provide insight into how antiviral and immunopathologic functions are regulated in the lung parenchyma. We have recently identified type II alveolar cells (AT2) as important regulators of immune responses to lung viral infections. AT2 are abundant epithelial cells present in the distal lung, and unlike most other nonhematopoietic cells, they constitutively express MHC class II (MHCII). AT2 MHCII seems to play an important protective role in the lung, as loss of MHCII on AT2 results in significantly higher morbidity and impaired recovery from influenza (flu) infection in mice. However, unexpectedly, AT2 do not efficiently present antigenic peptides via MHCII. Together this suggests that during viral infection, AT2 MHCII exhibits an active protective function and furthermore that AT2 are prevented from stimulating CD4+ T cells in the lung via MHCII. The experiments outlined in this proposal will elucidate the mechanisms underlying AT2 MHCII protection from flu disease as well as those limiting AT2 MHCII presentation to CD4+ T cells. Aim 1 will investigate the factors contributing to AT2 MHCII-mediated protection during flu infections by comparing flu-infected mice with and without AT2 MHCII and evaluating the effect of CD8+ T cell depletion, the phenotype and function of lung-infiltrating immune cells, virus titers, and lung pathology. Aim 2 will assess the mechanisms that limit AT2 MHCII antigen presentation, in particular evaluating the role of the canonical MHCII processing chaperones invariant chain and H2M in restricting AT2 MHCII presentation. These experiments will be complemented by a rigorous training plan focused on achieving my scientific, clinical, and professional goals. Specifically, this plan involves improving my knowledge of advanced laboratory techniques, ability to critically evaluate scientific work, and communication with collaborators and fellow scientists. Additionally, it includes strategies for refining my teaching, leadership, and patient care skills. My training will take place at the University of Pennsylvania, a research institution rich with diverse scientific resources and a highly collaborative atmosphere, under the guidance of the Medical Scientist Training Program as well as my PhD advisor who has an extensive history of mentoring trainees. The plans outlined in this proposal in combination with this environment will foster my development as a physician-scientist.

项目摘要：下呼吸道感染是全球死亡的主要原因。当前的疫苗尤其是包括肺病毒感染在内的此类感染的有针对性治疗稀疏有效。因此，迫切需要提高我们对抗病毒免疫反应的理解肺。肺病毒感染引起的发病率是由病毒诱导的和免疫介导的肺损伤引起的，自适应免疫细胞影响这两个过程。它们是病毒清除所必需的，但也是肺免疫病理学的主要原因。调节这些之间平衡的机制保护性和病理反应知之甚少。该提案的目的是提供见解在肺实质中如何调节抗病毒和免疫病理功能。我们最近确定了II型肺泡细胞（AT2）是对免疫反应的重要调节剂肺病毒感染。 AT2是远端肺中存在的丰富上皮细胞，与大多数其他不同它们非he骨细胞，它们组成型表达MHC II类（MHCII）。 AT2 MHCII似乎在玩在肺中重要的保护作用，因为MHCII在AT2上的损失导致发病率明显更高和从小鼠中流感（流感）感染恢复的障碍。但是，出乎意料的是，AT2不能有效地存在通过MHCII抗原肽。这共同表明，在病毒感染期间，AT2 MHCII表现出活性保护功能，此外，通过MHCII阻止AT2刺激肺中的CD4+ T细胞。该提案中概述的实验将阐明AT2 MHCII保护的机制免受流感疾病以及将AT2 MHCII呈现给CD4+ T细胞的疾病。 AIM 1将调查导致AT2 MHCII介导的保护在流感感染过程中的因素比较有或没有AT2 MHCII的流感感染小鼠，并评估CD8+ T细胞耗竭的作用，肺浸润的免疫细胞，病毒滴度和肺病理学的表型和功能。 AIM 2将评估限制AT2 MHCII抗原表现的机制，特别是评估了规范MHCII的作用加工伴侣不变链和H2M限制AT2 MHCII呈现。这些实验将通过一项严格的培训计划来补充，该计划的重点是实现我的科学，临床和专业目标。具体而言，该计划涉及提高我对高级实验室的了解技术，批判性评估科学工作的能力以及与合作者和合作伙伴的沟通科学家。此外，它还包括完善我的教学，领导和患者护理技能的策略。我的培训将在宾夕法尼亚大学进行，这是一家具有多种科学的研究机构在医学科学家培训的指导下，资源和高度协作的氛围课程以及我的博士顾问，他们拥有指导学员的悠久历史。概述的计划该建议与这种环境结合在一起将促进我作为医师科学家的发展。