Perrotta Marialuisa, Perrotta Sara, Carnevale Lorenzo, Migliaccio Agnese, Pallante Fabio, Nosalski Ryszard, Guzik Tomasz J, Fardella Stefania, Hirsch Emilio, Fardella Valentina, Zonfrilli Azzurra, Pacella Jacopo, Wymann Matthias P, Lembo Giuseppe, Carnevale Daniela
Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy.
Nat Commun. 2025 Jul 1;16(1):5818. doi: 10.1038/s41467-025-61009-4.
Activated immune cells infiltrate the vasculature during the pathophysiology of hypertension by establishing a vascular-immune interface that contributes to blood pressure dysregulation and organ failure. Many observations indicate a key role of CD8 T cells in hypertension but mechanisms regulating their activation and interplay with the cardiovascular system are still unknown. In murine model, here we show that a specific member of the phosphoinositide-3-kinases (PI3K) family of lipid kinases, PI3Kγ, is a key intracellular signaling of CD8 T cells activation and RANTES/CCL5 secretion in hypertension: CCL5-CCR5 signaling is crucial for the establishment of the vascular-immune interface in peripheral organs, lastly contributing to CD8 tissue infiltration, organ dysfunction and blood pressure elevation. Our studies identify PI3Kγ as a booster of effector CD8 T cell function, even in the absence of external stimuli. Lastly, an enhanced PI3Kγ signaling mediates the bystander activation of CD8 T cells and proves effective in transferring the hypertensive phenotype between mice.
在高血压的病理生理过程中，活化的免疫细胞通过建立血管 - 免疫界面浸润脉管系统，这会导致血压调节异常和器官衰竭。许多观察结果表明CD8 T细胞在高血压中起关键作用，但调节其活化以及与心血管系统相互作用的机制仍不清楚。在小鼠模型中，我们在此表明脂质激酶磷酸肌醇 - 3 - 激酶（PI3K）家族的一个特定成员PI3Kγ，是高血压中CD8 T细胞活化和RANTES/CCL5分泌的关键细胞内信号传导：CCL5 - CCR5信号传导对于外周器官中血管 - 免疫界面的建立至关重要，最终导致CD8组织浸润、器官功能障碍和血压升高。我们的研究确定PI3Kγ是效应CD8 T细胞功能的增强剂，即使在没有外部刺激的情况下也是如此。最后，增强的PI3Kγ信号传导介导CD8 T细胞的旁观者活化，并证明在小鼠之间传递高血压表型方面有效。
