Enhanced adenosinergic signaling and immune cell exhaustion after trauma

Abstract

Abstract Trauma is currently the leading cause of death in young adults, in some cases due to infection as a consequence of acquired immune suppression. The pathogenesis for this is poorly understood. Extracellular ATP released from cells during injury serves as a danger molecule, but is rapidly converted to AMP by the ectonucleotidase CD39; AMP is then hydrolyzed to immunosuppressive adenosine by CD73 ecto-5’-nucleotidase. Here, we studied the impact of purinergic signaling in trauma patients over time (day 0/1 after trauma (D1) vs day 2 after trauma (D2) vs controls undergoing elective surgery). We noted higher expression of Adenosine A2A- and A2B- receptor mRNA levels in blood PBMCs on D2 and later, when compared to D1 trauma patients and control samples. Analyses of BAL-derived mononuclear cells revealed decreases in CD39 activity in D1 trauma patients and marked decreases in CD73 activity in D2 trauma patients, when compared to controls. Notably, there was increased CD39 and CD73 expression in PBMC-derived CD8 T-cells of trauma patients, suggesting these cells as the prominent subset involved in the purinergic signaling during trauma. Importantly, CD39+CD8+cells from trauma patients displayed features of “immune exhaustion” phenotype (i.e. high PD-1 and Tim-3 levels) and exhibited less cytotoxicity. We conclude that the early phase after trauma is initially characterized by heightened systemic inflammation with boosted ATP-mediated signaling, linked with loss of CD39 activity. This is followed by an immunosuppressive phase characterized by enhanced adenosinergic signaling and by increase in exhausted CD39+CD8+cells, which might impair the innate immune responses and lead to increased susceptibility to infections in trauma patients.