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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.

Field of science

  • /medical and health sciences/basic medicine/immunology/autoimmune diseases
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/basic medicine/immunology/immunotherapy

Call for proposal

ERC-2010-AdG_20100317
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Address
1 Midland Road
NW1 1AT London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 2 499 998,20
Principal investigator
Caetano Maria Pacheco Pais Dos Reis E Sousa (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)

Beneficiaries (2)

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom
EU contribution
€ 2 499 998,20
Address
1 Midland Road
NW1 1AT London
Activity type
Research Organisations
Principal investigator
Caetano Maria Pacheco Pais Dos Reis E Sousa (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)
CANCER RESEARCH UK LBG
United Kingdom
Address
St John Street 407 Angel Building
EC1V 4AD London
Activity type
Research Organisations
Administrative Contact
Holly Elphinstone (Ms.)