DC-ACTIVATION · Functional characterization of indirect dendritic cell activation and its impact on adaptive immunity
FP7 — People (Marie Curie Actions)
- Duration
- 2010-03-31 → 2012-03-30
- EU contribution
- €181,351
- Participants
- 1
- Scheme
- MC-IEF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
During infection, recognition of the infectious microorganism by the innate immune system leads to dendritic cell (DC) activation. This process is essential for the induction of antigen-specific adaptive immune responses. DC can be activated directly by conserved pathogen molecules or indirectly by inflammatory mediators released by other cell types that recognized such molecules. However, recent studies revealed that inflammation cannot completely substitute for direct DC recognition of microbes and that indirect DC activation is insufficient for immunologic priming. We will explore which aspects of DC activation are dependent on direct microbial priming by microarray comparison of directly and indirectly activated DC. The aim is to identify the critical signals that are necessary and sufficient to convert resting DC into immunostimulatory antigen presenting cells that are fully competent to prime T cell responses. Moreover, we will determine whether the same rules apply for pattern recognition receptors other than toll-like receptors. Finally, the fate of T cells primed by indirectly activated DC will be investigated. Particularly, we will evaluate whether these cells have acquired any signature indicative of regulatory properties. Understanding the signals that initiate and regulate DC activation is critical to our ability to manipulate the immune system for vaccination and therapy.
Original text from CORDIS.
Participants
- CANCER RESEARCH UK LBG · LONDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union