Yan Lei, Chen Yumei, Yang Yilin, Han Yi, Tong Chaoyang
Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
Cell Death Discov. 2024 Jun 13;10(1):283. doi: 10.1038/s41420-024-02046-8.
CD8 T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8 T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8 T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8 T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8 T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8 T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8 T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8 T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.
CD8 T细胞耗竭是脓毒症诱导的急性呼吸窘迫综合征（ARDS）一个有前景的预后指标。脓毒症相关ARDS患者的HSP90AA1水平降低。然而，CD8 T细胞的变化是否与HSP90AA1基因编码的HSP90α相关尚不清楚。本研究旨在探讨HSP90α的调控机制及其对脂多糖（LPS）诱导的急性肺损伤（ALI）中CD8 T细胞耗竭的影响。在本研究中，通过构建ALI小鼠模型，我们发现LPS诱导ALI一周后，CD8 T细胞呈现耗竭特征。此时，CD8 T细胞的增殖和细胞因子释放减少。另一方面，抑制性共刺激因子PD-1和Tim-3增强。同时，HSP90α和STAT1的表达显著降低。体外研究表明，HSP90α刺激或抑制会影响CD8 T细胞耗竭表型。干扰STAT1会降低HSP90α的表达并损害其对CD8 T细胞的调节。免疫共沉淀结果表明，HSP90α可直接或间接结合TOX以调节TOX表达和下游信号转导。总之，通过抑制TOX介导的耗竭信号通路，HSP90α抑制了ALI中CD8 T细胞的耗竭。STAT1参与HSP90α的调节是必需的。
