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

• 批准号: 9907418
• 负责人: Sushila Toulmin
• 金额: $ 3.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9907418
• 关键词: AGTR2 gene; Ablation; Antigen Presentation; Antiviral Agents; Autoimmune Process; 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; Respiratory physiology; 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; immunoregulation; improved; in vivo; influenzavirus; insight; invariant chain; lung injury; mortality; novel; pathogen; phenotypic biomarker; prevent; receptor; response; skills; stem cells; success; trafficking; vaccine development

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：下呼吸道感染是世界范围内的主要死亡原因。当前疫苗 针对这些感染的靶向治疗，特别是肺部病毒感染， 灵验。因此，迫切需要提高我们对抗病毒免疫应答的理解， 肺。肺部病毒感染的发病是由病毒诱导和免疫介导的肺损伤引起的， 适应性免疫细胞影响这两个过程;它们是清除病毒所必需的，但它们 也是肺免疫病理学的主要原因。调节这些之间平衡的机制 保护性和病理性反应知之甚少。本提案的目的是提供见解 了解肺实质中抗病毒和免疫病理学功能是如何调节的。 我们最近发现II型肺泡细胞（AT 2）作为免疫反应的重要调节因子， 肺部病毒感染AT 2是存在于远端肺中的丰富的上皮细胞，并且与大多数其他上皮细胞不同， 在非造血细胞中，它们组成型表达MHC II类（MHCII）。AT 2 MHCII似乎发挥了 在肺中具有重要的保护作用，因为AT 2上MHCII的丧失导致显著更高的发病率， 小鼠流感感染后的恢复受损。然而，出乎意料的是，AT 2不能有效地呈现 抗原肽通过MHCII。总之，这表明在病毒感染期间，AT 2 MHCII表现出活性， 保护功能，此外，防止AT 2通过MHCII刺激肺中的CD 4 + T细胞。 本提案中概述的实验将阐明AT 2 MHCII保护的潜在机制， 流感疾病以及限制AT 2 MHCII呈递给CD 4 + T细胞的那些。 目的1将通过以下方法研究流感感染期间AT 2 MHCII介导的保护作用的因素： 比较有和没有AT 2 MHCII的流感感染小鼠并评估CD 8 + T细胞耗竭的效果， 肺浸润免疫细胞的表型和功能、病毒滴度和肺病理学。目标2将评估 限制AT 2 MHCII抗原呈递的机制，特别是评估典型MHCII的作用 加工分子伴侣不变链和H2 M以限制AT 2 MHCII呈递。 这些实验将辅以严格的训练计划，重点是实现我的科学， 临床和专业目标。具体来说，这个计划包括提高我对先进实验室的知识 技术，批判性地评估科学工作的能力，以及与合作者和研究员的沟通 科学家此外，它还包括完善我的教学，领导和病人护理技能的策略。我 培训将在宾夕法尼亚大学进行，这是一个拥有丰富多样科学知识的研究机构。 在医学科学家培训的指导下， 计划以及我的博士生导师谁拥有广泛的指导学员的历史。概述的计划， 这一建议与这种环境相结合，将促进我作为一名物理学家和科学家的发展。