Simon Hirschberger, Martin B. Müller, Hannah Mascolo, Melissa Seitz, Stefan Nibler, David Effinger, Kun Lü, J Buch, Martin Bender, Tobias Kammerer, Sven Peterß, Karin Kleigrewe, Miriam Abele, Teresa K. Barth, Olga Kushnir, Axel Imhof, Steffen Dietzel, Bernd Wegener, Ralf Sowa, Frank Vogel, Peter Lamm, Roland Tomasi, Kristian Unger, Markus Sperandio, Erich Kilger, Simone Kreth, Max Hübner
Cytotoxic T cell (CTL) dysfunction is a hallmark of immune paralysis after major surgery, increasing susceptibility to severe nosocomial infections and contributing to mortality in critically ill patients. The mechanisms remain poorly understood. We demonstrate that reactive oxygen species (ROS) released by myeloid-derived suppressor cells (MDSC) transiently emerging after surgery, drive perioperative CTL immunoparalysis. These ROS damage CTL mitochondria, triggering secondary mitochondrial ROS amplification and overwhelming antioxidant defenses. The resulting oxidative cascade impairs oxidative phosphorylation and suppresses CTL effector function. Concurrently, stress-induced mitochondrial hyperfusion disrupts fission-dependent translocation to the immunological synapse, exacerbating bioenergetic failure. MitoTEMPO, a mitochondria-targeted antioxidant, partially mitigates these effects, highlighting mitochondrial stabilization as a potential strategy to prevent perioperative immune dysfunction.