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Cross-species characterisation of CD8alpha+ dendritic cells and their role in immune regulation

Objective

Dendritic cells (DC) are a heterogeneous family of leucocytes with important functions in immunity. Little is known about the role of distinct DC subtypes in vivo. In the mouse, a subset known as CD8alpha+ DC has been argued to represent a discrete DC lineage with specialised properties. These include a superior capacity for presenting exogenous antigens to CD8+ and CD4+ T cells, which makes CD8alpha+ DC an attractive target in vaccination and tolerisation. However, it is unclear whether CD8alpha+ DC fulfill unique and non-redundant roles in the immune system. In addition, the reported restriction of CD8alpha+ DC to thymus and secondary lymphoid organs is hard to reconcile with their documented capacity to act as presenting cells for antigens outside those organs. Finally, CD8alpha+ DC have not been identified in humans, greatly restricting their use in immunotherapy. In this proposal, we exploit the recent finding that DNGR-1 (CLEC9A) acts as a new and specific marker for the CD8alpha+ lineage to address these issues. We will generate DNGR-1-Cre mice as a universal tool to manipulate gene expression in the subset. We will use such mice to render CD8alpha+ DC sensitive to toxic proteins that permit constitutive or transient ablation of the subset for functional studies. DNGR-1-Cre mice will further be used to express fluorescent proteins in CD8alpha+ DC, allowing tracing of the lineage in vivo, both in lymphoid and non-lymphoid organs. Finally, we will use the DNGR-1 marker to identify and characterise putative CD8alpha+ DC equivalents in humans. The results from this proposal will illuminate the function of CD8alpha+ DC across species and open the door for using this intriguing DC subset in immunotherapy of cancer, infectious and autoimmune diseases.

Call for proposal

ERC-2010-AdG_20100317
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Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Address
1 Midland Road
NW1 1AT London
United Kingdom

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Activity type
Research Organisations
Administrative Contact
Stéphane Maikovsky (Mr.)
Principal investigator
Caetano Maria Pacheco Pais Dos Reis E Sousa (Dr.)
EU contribution
€ 2 499 998,20

Beneficiaries (2)

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom
EU contribution
€ 2 499 998,20
Address
1 Midland Road
NW1 1AT London

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Activity type
Research Organisations
Administrative Contact
Stéphane Maikovsky (Mr.)
Principal investigator
Caetano Maria Pacheco Pais Dos Reis E Sousa (Dr.)
CANCER RESEARCH UK
United Kingdom
Address
St John Street 407 Angel Building
EC1V 4AD London

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Activity type
Research Organisations
Administrative Contact
Holly Elphinstone (Ms.)