Unique CD8+ T Cell Priming by Antigen Presenting Plasmacytoid Dendritic Cells Compared to Conventional Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play a crucial role in orchestrating immune responses, especially against viral infections, and have traditionally been well recognized for their ability to produce type I and type III interferons. However, recent discoveries reveal pDCs to be heterogeneous with more complex functions that include antigen uptake, processing, and presentation. We investigated the antigen cross-presentation ability of pDCs and their role in CD8+ T cell priming, a subject of ongoing debate. Utilizing a novel culturing system of CD8+ T cells and autologous pDCs derived from human blood circulating CD34+ hematopoietic stem and progenitor cells (cHSPCs), we demonstrate that pDCs can efficiently prime CD8+ T cells through cross-presentation, thereby contributing to their expansion and cytotoxic activity. The pDCs' antigen presentation ability is comparable to that of monocyte-derived dendritic cells (moDCs), which are traditionally known for their efficient antigen presentation capacity. Bioinformatic analysis of the primed CD8+ T cells to uncover their transcriptomic profile following priming by pDCs versus moDCs, revealed distinct genetic signatures, indicating that pDCs prime CD8+ T cells differently than cDCs. These findings challenge the traditional view of pDCs as mere IFN-producing cells, highlighting their significant role in antigen presentation and T cell activation. Overall design: CD8+ T cells sorted after co-cultured with cHSPC-pDCs and moDCs stimulated with TLR7 or TLR4 agonist, respectively, and subsequently incubated with or without antigen