Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury

内皮抗原呈递给 T 细胞作为流感诱导的急性肺损伤的致病机制

• 批准号: 10583575
• 负责人: Lianghui Zhang
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583575
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Acute respiratory failure; Antigen Presentation; Antigen-Presenting Cells; Antigens; Blood Vessels; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cessation of life; Complication; Data; Development; Developmental Gene; Endothelial Cells; Endothelium; Equilibrium; Granzyme; Heterogeneity; Histocompatibility Antigens Class II; Homeostasis; Hospitalization; Hyperactivity; I-antigen; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Lung; Major Histocompatibility Complex; Mechanical ventilation; Mediator; Natural regeneration; Parasitic infection; Pathogenicity; Pathway interactions; Patients; Play; Poly I-C; Process; Pulmonary Edema; Regulator Genes; Research; Role; SOX17 gene; Secondary to; Severities; Signal Transduction; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Vascular Endothelial Cell; Viral; Virulence Factors; Virus; Work; allograft rejection; cell injury; cell regeneration; cytotoxic CD8 T cells; endothelial regeneration; epithelial injury; immunoregulation; in vivo; influenza epidemic; influenza infection; influenzavirus; injured; insight; lung injury; lung vascular injury; mortality; mouse model; neutralizing antibody; new therapeutic target; novel; overexpression; prevent; regenerative; seasonal influenza; single-cell RNA sequencing; targeted treatment; transcription factor; viral RNA

Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury. ABSTRACT Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a form of acute respiratory failure with substantial mortality, characterized by massive loss of lung vascular barrier function due to excessive inflammation, endothelial cell injury and death. Up to 20% of hospitalized patients with an influenza infection develop ALI or ARDS and require mechanical ventilation. Unfortunately, there are no targeted therapies available to prevent death secondary to ALI/ARDS. Therefore, it is imperative to understand the mechanisms by which the influenza virus induces ALI and identify novel therapeutic targets. Lung epithelial injury has been well studied in influenza infections, however the mechanisms of endothelial injury induced by influenza virus are still poorly understood despite the fact that endothelial injury is a central feature of ALI/ARDS. Besides their role in maintaining vascular barrier function, vascular endothelial cells (ECs) play an important role in regulating inflammation. Our novel supporting data indicate that lung ECs consist of at least two major subpopulations – pro-inflammatory ECs and pro-regenerative or developmental ECs during baseline conditions. Developmental lung EC express the developmental transcription factor Sox17 which regenerates the injured endothelium during infections. Inflammatory lung ECs, on the other hand, express low levels of Sox17 and instead express higher levels of the major histocompatibility complex (MHC) class I and II molecules. H1N1 infection significantly upregulates the expression of MHC class I and II molecules in ECs. The infection also significantly increases the number of CD8+ cytotoxic T lymphocytes in the lung. Therefore, we hypothesize that inflammatory ECs act as antigen presenting cells and present antigens to T lymphocytes and thus promote acute lung injury. We will study whether expression of developmental and regenerative transcription factor Sox17 prevents the activation of inflammatory signaling and antigen presentation. We will also assess whether the lung ECs present antigens to CD8+ and CD4+ T lymphocytes by MHC class I and II molecules during H1N1-induced ALI. Finally, we will study whether the activation of CD8 cytotoxic T cells induces EC death via the release of Granzyme B and cleavage of its intracellular target Gasdermin E during H1N1-induced ALI. Here, we propose a novel mechanism of endothelial cells as antigen presenting cells in influenza-induced ALI/ARDS. Unravelling this mechanism will provide new insights and identify novel therapeutic targets into virus-induced ALI.

内皮细胞抗原呈递给T细胞是流感急性肺损伤的致病机制 损伤 摘要 急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS）是一种急性呼吸衰竭， 死亡率高，特征是由于过度的肺血管屏障功能丧失， 炎症、内皮细胞损伤和死亡。高达20%的流感感染住院患者 发生ALI或ARDS，需要机械通气。不幸的是，目前还没有针对性的治疗方法 预防继发于ALI/ARDS的死亡。因此，必须了解 流感病毒诱导ALI并鉴定新的治疗靶点。肺上皮损伤已得到充分研究 然而，在流感感染中，流感病毒诱导的内皮损伤机制仍然不清楚， 尽管事实上内皮损伤是ALI/ARDS的中心特征，除了他们的角色， 血管内皮细胞（vascular endothelial cells，ECs）是维持血管屏障功能的重要细胞， 炎症我们新的支持数据表明，肺EC至少由两个主要亚群组成- 促炎EC和促再生或发育EC。发育 肺EC表达发育转录因子Sox 17，该因子可使受损的内皮再生， 感染.另一方面，炎症性肺EC表达低水平的Sox 17，而表达高水平的Sox 17。 主要组织相容性复合体（MHC）I类和II类分子的水平。H1N1感染严重 上调EC中MHC I类和II类分子的表达。感染也显著增加了 肺中CD 8+细胞毒性T淋巴细胞的数量。因此，我们假设炎性内皮细胞作为 抗原呈递细胞将抗原呈递给T淋巴细胞，从而促进急性肺损伤。我们将研究 发育和再生转录因子Sox 17的表达是否阻止了 炎症信号传导和抗原呈递。我们还将评估肺内皮细胞是否呈递抗原， 在H1N1诱导的ALI期间，通过MHC I类和II类分子的CD 8+和CD 4 + T淋巴细胞。最后，我们将研究 CD 8细胞毒性T细胞的活化是否通过颗粒酶B的释放和切割诱导EC死亡 在H1N1诱导的ALI中其细胞内靶Gasdermin E的表达。在这里，我们提出了一种新的机制， 内皮细胞作为抗原呈递细胞在流感诱导的ALI/ARDS中的作用。解开这一机制将 为病毒诱导的ALI提供新的见解并确定新的治疗靶点。