Activation of human CD141 and CD1c dendritic cells in vivo with combined TLR3 and TLR7/8 ligation.

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141 and CD1c myeloid and CD123 plasmacytoid dendritic cells (DC) develop from human cord blood CD34 cells in immunodeficient mice. CD141 DC are the human equivalents of murine CD8 /CD103 DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies.

Human CD141 Dendritic Cell and CD1c Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice .

Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34 hematopoietic stem cells. These "humanized" mice are useful models to study human immunology and human-tropic infections, autoimmunity, and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross-reactivity of many growth factors and cytokines between species.

Human Blood CD1c Dendritic Cells Promote Th1 and Th17 Effector Function in Memory CD4 T Cells.

Dendritic cells (DC) initiate the differentiation of CD4 helper T cells into effector cells including Th1 and Th17 responses that play an important role in inflammation and autoimmune disease pathogenesis. In mice, Th1 and Th17 responses are regulated by different conventional (c) DC subsets, with cDC1 being the main producers of IL-12p70 and inducers of Th1 responses, while cDC2 produce IL-23 to promote Th17 responses. The role that human DC subsets play in memory CD4 T cell activation is not known.

Targeting CLEC9A delivers antigen to human CD141 DC for CD4 and CD8T cell recognition.

DC-based vaccines that initiate T cell responses are well tolerated and have demonstrated efficacy for tumor immunotherapy, with the potential to be combined with other therapies. Targeting vaccine antigens (Ag) directly to the DCs in vivo is more effective than cell-based therapies in mouse models and is therefore a promising strategy to translate to humans. The human CD141 DCs are considered the most clinically relevant for initiating CD8 T cell responses critical for killing tumors or infected cells, and they specifically express the C-type lectin-like receptor CLEC9A that facilitates presentation of Ag by these DCs.