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

点击翻译按钮获取中文摘要

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.