PI3Kγ signaling controls trafficking of CD8+ T cells between lymphoid and non-lymphoid organs and drives hypertension in a murine model

Marialuisa Perrotta, Sara Perrotta, Lorenzo Carnevale, Agnese Migliaccio, Fabio Pallante, Ryszard Nosalski, Tomasz J. Guzik, Stefania Fardella, Emilio Hirsch, Valentina Fardella, Azzurra Zonfrilli, Jacopo Pacella, Matthias P. Wymann, Giuseppe Lembo and Daniela Carnevale ()
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Marialuisa Perrotta: “Sapienza” University of Rome
Sara Perrotta: IRCCS Neuromed
Lorenzo Carnevale: IRCCS Neuromed
Agnese Migliaccio: IRCCS Neuromed
Fabio Pallante: IRCCS Neuromed
Ryszard Nosalski: University of Edinburgh
Tomasz J. Guzik: University of Edinburgh
Stefania Fardella: IRCCS Neuromed
Emilio Hirsch: University of Torino
Valentina Fardella: IRCCS Neuromed
Azzurra Zonfrilli: “Sapienza” University of Rome
Jacopo Pacella: IRCCS Neuromed
Matthias P. Wymann: University of Basel
Giuseppe Lembo: “Sapienza” University of Rome
Daniela Carnevale: IRCCS Neuromed

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61009-4

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