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

项目概述：下呼吸道感染是全球主要的死亡原因。当前的疫苗 对这种感染的针对性治疗，特别是肺部病毒感染，很少，而且效果很差。 很有效。因此，迫切需要提高我们对抗病毒免疫反应的理解。 阿龙。肺部病毒感染的发病率既有病毒诱导的，也有免疫介导的肺损伤， 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 也是肺部免疫病理的主要原因之一。调节这两者之间平衡的机制 保护性反应和病理反应知之甚少。这项建议的目的是提供见解 研究抗病毒和免疫病理功能是如何在肺实质中调节的。 我们最近发现II型肺泡细胞(AT2)是免疫反应的重要调节者。 肺部病毒感染。AT2是一种存在于肺远端的丰富的上皮细胞，与大多数其他细胞不同。 非造血细胞结构性地表达MHC II类(MHCII)。在2岁的时候，MHCII似乎在玩一场 在肺中起着重要的保护作用，因为AT2上MHCII的缺失导致显著更高的发病率和 小鼠从流感(流感)感染中恢复受阻。然而，出乎意料的是，AT2没有有效地呈现 通过MHCII获得抗原肽。综上所述，这表明在病毒感染期间，AT2 MHCII表现出活跃的 此外，AT2通过MHCII刺激肺中的CD4+T细胞而被阻止。 本提案中概述的实验将阐明AT2 MHCII保护机制。 流感疾病以及限制AT2 MHCII呈递给CD4+T细胞的疾病。 目的1将通过以下方式调查AT2 MHCII介导的流感感染期间保护的因素 比较感染流感的小鼠和不感染AT2 MHCII的小鼠，评估CD8+T细胞去除的效果 肺浸润性免疫细胞的表型和功能、病毒滴度和肺病理。目标2将评估 限制AT2 MHCII抗原提呈的机制，特别是评估规范MHCII的作用 伴侣不变链和H_2M在限制AT2 MHCII提呈中的作用 这些实验将得到一项严格的培训计划的补充，重点是实现我的科学、 临床目标和职业目标。具体地说，这个计划涉及到提高我的高级实验室知识 技术，批判性评估科学工作的能力，以及与合作者和同事的沟通 科学家。此外，它还包括完善我的教学、领导力和病人护理技能的策略。我的 培训将在宾夕法尼亚大学进行，这是一个研究机构，拥有丰富的科学知识 资源和高度协作的氛围，在医学科学家培训的指导下 还有我的博士生导师，他有指导学员的丰富历史。中概述的计划 这项提议与这种环境相结合，将促进我作为一名内科科学家的发展。

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.