Abstract Text: Our study addresses the critical issue of allograft rejection in kidney transplantation, where current immunosuppressive drugs pose significant risks. We propose a novel approach to cell therapy using autologous tolerogenic dendritic cells (ATDC) to promote graft acceptance. Based on our encouraging results in rodents, our team developed a GMP-compliant ATDC manufacturing process, and this cell therapy was evaluated in a first-in-man phase I/II clinical trial. In vitro characterization of ATDC highlighted that these cells exhibit enhanced glycolytic activity, and the abundant produced lactate was responsible for the suppression of CD4+ T cell proliferation and activation. In our trial, reduced CD8+ T cell activation and increased FoxP3 expression were observed in the circulating immune cells of kidney transplant recipients treated with ATDC. Focusing on the regulation of CD8+ T cells by ATDC, our in vitro experiments demonstrated that ATDC-derived metabolites suppress naive, effector, and TEMRA CD8+ T cell proliferation. Unlike CD4+ T cells, lactate was not involved in this suppression. However, the critical role of indoleamine-2,3-dioxygenase produced by ATDC to suppress CD8+ cells was evidenced using a specific inhibitor, establishing tryptophan deficiency as a mediator of CD8+ T cell proliferation inhibition. Metabolic and transcriptomic analyses highlighted that the ATDC environment promotes oxidative phosphorylation in naive CD8+ T cells, associated with their reduced activation. Moreover, ATDC decreases their migratory capacity through a contact-dependent mechanism. In conclusion, our findings support the efficacy of ATDC as a therapeutic strategy in kidney transplantation, particularly in suppressing CD8+ T cell-mediated allograft rejection.
