Complement-Mediated Exosome Function in Transplantation

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Project Summary T cell mediated graft rejection remains a critical barrier to long-term graft health and survival. Post-transplant complement-induced priming of T cells and the transfer of donor major histocompatibility complexes (MHC) to recipient dendritic cells (DCs) by graft-released exosomes (commonly referred to as “cross dressing”) are both mechanistically involved in the generation of anti-donor cellular immunity. Our preliminary data newly implicate mannose binding lectin (MBL) pathway-dependent complement activation as necessary mediator for complement opsonization of exosomes and exosome-mediated donor MHC delivery to recipient DCs. Together with our prior observation that recipient MBL pathway complement activation is required for generation of robust anti-donor T cell responses and costimulatory-blockade resistant graft rejection, these data lead to our central hypothesis that post transplant MBL pathway-initiated complement activation deposits complement opsonins on exosomes, which bind to recipient DCs via complement receptors, and that this process optimizes DC “cross dressing” to permit semi-direct pathway anti-donor T cell immunity and ultimately allograft rejection. We will test this hypothesis in two specific aims. In aim 1 we will study the mechanisms required for complement activation on exosomes, characterize the effect of complement opsonins on exosome binding to recipient DCs, and test the role of DC-expressed complement receptors in our model. In aim 2 we will test for links between complement-mediated DC “cross dressing” and post-transplant anti-donor T cell immunity and transplant outcomes. The findings will be significant because a) they will provide fundamental insights into the biology of exosome function, b) provide mechanistic links between exosomes, complement, and adaptive T cell immunity, and c) potentially identify novel treatment strategies and therapeutic targets to improve transplant outcomes. Our proposal is conceptually innovative and tests a novel paradigm linking exosome function and complement activation that may have broad implications beyond the field of transplantation.