ATP-mediated signaling of P2X7 receptors controls donor extracellular vesicle release and MHC cross-decoration after allotransplantation

After skin allotransplantation, intercellular transfer of donor MHC molecules mediated primarily by extracellular vesicles (EVs) released by the allograft is known to contribute to semi-direct 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 (DAMPs). Among these DAMPs, extracellular ATP plays a key role in innate inflammation through binding to P2X7 receptors. Indeed, this process leads to the activation of the NLRP3 inflammasome and subsequent production and release of inflammatory cytokines and EVs. This prompted us to evaluate the influence of innate inflammation triggered by ATP-mediated signaling of P2X7 receptors 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 MHC 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.