Liver-derived mitochondria drive CD8 T-cell dysfunction, alter purinergic signaling and impair bacterial clearance in the lung in vivo

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Abstract Trauma is the leading cause of death in young adults. The pathogenetic mechanisms resulting in posttraumatic immunosuppression with increased susceptibility to infection remain unclear. Mitochondria (MT) are released by cells after trauma and can generate danger molecules, such as extracellular ATP (eATP). The vascular and immune cell ectonucleotidase CD39 scavenges eATP to generate immunosuppressive derivatives such as adenosine. Here, we examined the role of eATP generated by exogenous mitochondria in modulating the immune response and provoking immunosuppression in the context of experimental pneumonia models. ATP probes and MitoSOX revealed that liver-derived MT generate ATP and ROS ex vivo. When injected into recipient mice, MT isolated from mouse liver induced upregulation of CD39 and CD73 expression on circulating CD8 T cells and promoted immune cell exhaustion. Next, wild-type mice were injected intraperitoneally with liver MT, followed by intratracheal instillation of pathogenic S. aureus. Mice receiving MT were unable to clear bacteria, as demonstrated by elevated CFU counts in the bronchoalveolar lavage, when compared to mice with bacterial instillation alone. Histological analysis confirmed more pronounced lung injury with infiltration of inflammatory neutrophils in mice administered both MT and bacteria, when compared to mice instilled only with bacteria. Lastly, the MT injection with concomitant bacteria administration resulted in loss of lung-derived CD8 T-cells. Our data indicate that ATP generation by exogenous mitochondria boost CD39 expression in circulating CD8 T-cells and drive dysfunctional immune responses in mice that result in increased susceptibility to bacterial infection of the lungs.