Type 1 conventional dendritic cells (cDC1s) and plasmacytoid dendritic cells (pDCs) are thought to be critical for anti-tumor or antiviral immunity. In vitro differentiation systems have unlocked the ability to produce large numbers of these cells. However, a method is lacking to systematically identify the cell-intrinsic factors controlling their differentiation and functions that remain therefore poorly understood, in contrast to the situation in mice. Here, the inventors developed a workflow for efficient gene silencing and its tracing in human cDC1s/pDCs generated in vitro. They demonstrate the key role of IRF8 in their development, and of IRF7/MyD88 in human pDC production of interferons-α/λ. They found that SAMHD1 and RAB7B promote human cDC1 differentiation, while SEPT3 promotes human pDC differentiation. Finally, they identified that the transcription factors ID2 and DC-SCRIPT versus BCL11A promote cDC1 versus pDC development respectively. This approach will enable broader genetic screens to advance our understanding of human cDC1s/pDCs and harness them against viral infections or cancer.
Thus, the present invention relates to a method for inducing the differentiation of human hematopoietic stem cells into type 1 conventional dendritic cells or plasmacytoid dendritic cells, while genetically manipulating the hematopoietic stem cells to modulate the differentiation and/or functions of their dendritic cell progeny.