Conventional Dendritic Cells – Ecology, Diversity, and Function

ongoing

Effective T cell responses are critical for the efficacy of vaccination and cancer immunotherapy; therefore, the manipulation of conventional dendritic cells (cDCs) offers great potential for improved therapies as these cells play a key role in the activation and regulation of T cell function. However, cDCs are a diverse group of cells whose function is incompletely understood. Previous attempts at targeting cDCs therapeutically have been underwhelming perhaps as a result of not targeting the right cell subset specifically. The goal of this proposal therefore is to reveal the functional properties of the different cDC lineages during type 1 and type 2 immunity and to understand how the ecology of cDC subsets is regulated to meet the functional demands of tissues undergoing different types of inflammation. I propose that studying the cDC subsets that enhance cytotoxic T cell responses against viruses in type 1 immunity and those that enhance parasite clearance and tissue repair in type 2 immunity against nematodes will help to identify those cDC subsets that need to be either triggered or inhibited to improve tumour control. Therefore, we will use well-defined models of type 1 and type 2 immunity to reveal the diversity of these cells during inflammation. Furthermore, we will generate new mouse models to target cDCs subsets specifically to study their functional properties and to reveal how these functional properties are instructed. In this regard, we will address how subset specification is regulated distally, by a novel inter-organ communication axis (lung-bone marrow) that could tune the host immune system to ever-evolving challenges. Finally, as a proof of concept, we will use transplantable and orthotopic cancer models to unravel beneficial and detrimental cDC subsets in the immune response against cancer. cDCFun will open new avenues for the design of better vaccines and immunotherapies that harness the functional properties of specific subsets of cDCs.