Adenosine triphosphate-mediated signaling of P2X7 receptors controls donor extracellular vesicle release and major histocompatibility complex cross-decoration after allotransplantation

After skin allotransplantation, intercellular transfer of donor major histocompatibility complex molecules mediated primarily by extracellular vesicles (EVs) released by the allograft is known to contribute to semidirect and indirect activation of alloreactive T cells involved in graft rejection. At the same time, there is ample evidence showing that initiation of adaptive alloimmunity depends on early innate inflammation caused by tissue injury and subsequent activation of myeloid cells (macrophages and dendritic cells) recognizing danger-associated molecular patterns. Among these danger-associated molecular patterns, extracellular adenosine triphosphate plays a key role in innate inflammation by binding to P2X7 receptors (P2X7Rs). Indeed, this process leads to the activation of the Nod-like receptor protein 3 inflammasome and the subsequent production and release of inflammatory cytokines and EVs. This prompted us to evaluate the influence of innate inflammation triggered by adenosine triphosphate-mediated signaling of P2X7Rs on EV release by donor cells after skin transplantation in mice. In this article, we show that inhibition of P2X7R signaling suppresses both EV release and major histocompatibility complex cross-decoration of leukocytes and prolongs skin allograft survival in mice. This study reveals a novel aspect of the role of innate immunity in allotransplantation.