The DC1 conundrum: Do type I dendritic cells make or break allograft tolerance?

True immunologic tolerance in solid organ transplantation (SOT) confers long-term allograft survival without the need for immunosuppression. Type 1 conventional dendritic cells (DC1s) have emerged as a cell type of particular interest in this context, owing to their unique transcriptional programming, specialization in cross-presentation, and indispensable role in maintaining self-tolerance. DC1s have traditionally been studied for their potent stimulatory role in tumor and viral immunology, whereas most dendritic cell (DC)-based tolerance research has historically focused on the monocyte-derived DC. A growing body of work highlights a duality of DC1s in both promoting and undermining allotolerance, as tissue microenvironment, antigen load, signal integration, and cellular crosstalk all contribute to a complex landscape of DC1 functionality. Recent advances in DC biology have enabled precise investigation of DC function and ontogeny, and accumulating evidence supports a subset-specific, tolerogenic role of DC1s in SOT. Moving beyond murine models, recent early phase clinical trials have demonstrated compelling patient safety and efficacy data for tolerogenic DC-based cellular therapy in SOT. In this review, we discuss the seemingly paradoxical discoveries of DC1s' supportive and antagonistic roles in allotolerance and consider emerging data highlighting their potential capabilities as a novel cellular therapy in SOT.