Requirements and mechanisms of alloantigen-induced cardiac allograft survival by cDC1s

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PROJECT SUMMARY/ABSTRACT Heart transplantation is currently the only treatment for advanced stage heart failure and as such, the volume of transplants performed globally continues to increase. Advances in surgical technique and available immunosuppression have improved patient survival acutely, however the same cannot be said years after transplantation. Immune mediated pathologies such as chronic allograft vasculopathy result in graft failure and significant morbidity from prolonged use of immunosuppressant medication including renal dysfunction, diabetes, and malignancy, continue to be experienced by patients. Therefore, improved strategies to promote survival of the cardiac allograft are necessary. A great deal of research has sought to identify the cellular actors responsible for cardiac allograft rejection and tolerance. In the setting of rejection, the adaptive immune response has emerged in a leading role, specifically CD4+ and CD8+ T cells. Importantly, T cells are not solo performers but instead require instruction provided by antigen presenting cells, predominantly dendritic cells (DCs). Once considered a homogenous population, DCs are now recognized for their distinct ontogeny and functional roles which determine DC subset identity. Conventional DC 1 cells (cDC1s) are powerful mediators of the immune response and have been shown to be critical for the promotion of central tolerance. Yet no work on the subset specific role of cDC1s in solid organ transplantation has been performed and our understanding of cDC1s in peripheral tolerance remains in its infancy. Importantly, my preliminary data implicate cDC1s as necessary in donor-induced tolerization strategies that result in long term cardiac allograft survival. Tolerization strategies utilizing infused donor antigen and costimulation blockade (CoB) produce long term cardiac allograft survival in murine and nonhuman primate models, though little is known as to how exposure of donor alloantigen influences tolerance induction. This proposal hypothesizes that during a donor-induced tolerance strategy, the cDC1 subset is necessary to promote peripheral immunological hyporesponsiveness towards cardiac allografts through processing of alloantigen, modulation of surface marker expression, and metabolic transcriptional reprogramming. This hypothesis will be tested using mouse models of cDC1 deletion and heterotopic heart transplantation alongside functional (palpation, echocardiography) and cellular (flow cytometry, histology) analysis. Additionally, single-cell transcriptomics of splenic DCs after in vivo allo- and iso- infusion in the presence of CoB coupled with in vitro experimentation will help unveil cDC1 specific programming that promote a tolerogenic allospecific response. Thus, the proposed studies will identify targetable pathways to enhance immunologic tolerance and improve cardiac allograft survival.