Final Report Summary - DC-ACTIVATION (Functional characterization of indirect dendritic cell activation and its impact on adaptive immunity)
Project context and objectives
The main objective of this project was to characterise receptors and signalling pathways that lead to dendritic cell activation.
Work performed
We focused our efforts on investigating the action mechanism of DNGR-1. DNGR-1 is a receptor for necrotic cells that contributes to the cross-priming of cytotoxic T cells against dead cell-associated antigens. DNGR-1 is restricted to dendritic cells (DCs) in both mouse and human, and signals via Syk, suggesting that its function might be to activate DCs in response to encountering cell corpses. Surprisingly, however, we demonstrated that DNGR-1 signalling does not activate mouse DCs or other myeloid cells. Rather, its role in cross-priming correlates with its ability to divert necrotic cell cargo into a recycling endosomal compartment, which favours cross-presentation.
Main results
We have shown that DNGR-1 regulates cross-priming, not only in non-infectious settings, such as upon immunisation with antigen-bearing dead cells, but also in highly immunogenic situations, such as after a mouse is infected with herpes simplex virus type 1. The existence of a dedicated receptor for cross-presentation of cell-associated antigens and its demonstrable impact on antiviral responses in mice underscores the importance of cross-priming in immunity and suggests that antigenicity and adjuvanticity can in some instances be decoded by distinct innate immune receptors. As DNGR-1 specifically marks a human DC subset with cross-presentation ability, it may act as a major determinant of human immune responses to virus infections and to vaccination.
The main objective of this project was to characterise receptors and signalling pathways that lead to dendritic cell activation.
Work performed
We focused our efforts on investigating the action mechanism of DNGR-1. DNGR-1 is a receptor for necrotic cells that contributes to the cross-priming of cytotoxic T cells against dead cell-associated antigens. DNGR-1 is restricted to dendritic cells (DCs) in both mouse and human, and signals via Syk, suggesting that its function might be to activate DCs in response to encountering cell corpses. Surprisingly, however, we demonstrated that DNGR-1 signalling does not activate mouse DCs or other myeloid cells. Rather, its role in cross-priming correlates with its ability to divert necrotic cell cargo into a recycling endosomal compartment, which favours cross-presentation.
Main results
We have shown that DNGR-1 regulates cross-priming, not only in non-infectious settings, such as upon immunisation with antigen-bearing dead cells, but also in highly immunogenic situations, such as after a mouse is infected with herpes simplex virus type 1. The existence of a dedicated receptor for cross-presentation of cell-associated antigens and its demonstrable impact on antiviral responses in mice underscores the importance of cross-priming in immunity and suggests that antigenicity and adjuvanticity can in some instances be decoded by distinct innate immune receptors. As DNGR-1 specifically marks a human DC subset with cross-presentation ability, it may act as a major determinant of human immune responses to virus infections and to vaccination.