*Purpose: Dendritic cells (DCs) are antigen-presenting cells (APCs) important for initiating and coordinating the immune response. Plasmacytoid dendritic cells (pDCs) are a subset of DCs and multiple studies report a tolerogenic phenotype of immature pDCs.

*Methods: Using a murine cardiac allograft transplant model, our work demonstrates that intravenous injection of donor pDCs prior to transplantation prolong cardiac allograft survival, while donor conventional dendritic cells (cDC) have no effect on allograft prolongation. Additionally, our lab developed a novel murine model of vascularized composite allograft (VCA) transplantation which has a more robust immune response than solid-organ transplantation. In this highly immunogenic model, our work shows evidence of delayed graft rejection upon intravenous injection of donor pDCs. Using mass cytometry to profile the recipient immune response to VCA, we find evidence that pDC treatment and allograft prolongation correlates with upregulation of myeloid-derived suppressor cells.

*Results: To determine factors unique to the tolerogenic phenotype of pDCs we performed a microRNA (miRNA) microarray, and our results show that six miRNAs of the miR-181 family are upregulated in pDCs compared to cDCs. Likewise, pDCs deficient in miR-181a fail to prolong allograft survival. Transcriptome analysis of wild-type versus miR-181a deficient pDCs revealed statistically significant downregulation of multiple genes in miR-181a deficient mice that are related to immune co-stimulation and signaling. We report that Semaphorin 4a, which is involved in immunomodulation and is required for the function and stability of regulatory T (Treg) cells, is decreased in miR-181 deficient pDCs.

*Conclusions: Together our results show a critical role for miR-181 regulating the tolerogenic potential of pDCs which may be potentially utilized for advancing strategies to prolong allograft survival.

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