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

Final Report Summary - DCSUBSET (Cross-species characterisation of CD8alpha+ dendritic cells and their role in immune regulation)

Classical dendritic cells (cDCs) are leucocytes that play a key role in innate immunity as well as the initiation and regulation of T cell responses. cDCpoiesis starts with commitment of a bone marrow (BM) haematopoietic progenitor, known as the classical DC precursor (CDP), to the cDC lineage. CDPs then give rise to pre-cDCs that exit the BM via the blood and seed tissues to give rise to the two major types of fully-differentiated cDCs, the cDC1 and cDC2 subsets. Our work under this project has centred on utilising DNGR-1 (aka CLEC9A) as a marker to identify and classify cDCs. We found that DNGR-1 is highly expressed by fully-differentiated mouse DCs of the cDC1 subtype, which depend on the transcription factor Batf3 for their development, and that DNGR-1 can be used to identify them across multiple mouse tissues. We then used DNGR-1 as a marker to identify the human counterparts of mouse cDC1s. We proved that human DNGR-1+ cDC1 also require BATF3 for their differentiation in vitro, helping establish the equivalence of DC subtypes across species and opening the door to translating mouse findings into clinical application. In more recent work, we questioned whether human cDC1 always descend from a common myeloid precursor (CMP). Surprisingly, we found that human cDC1 can also originate from a human lymphoid-committed precursor and that cDC1 from a CMP or a lymphoid precursor are identical. These resuls underscore the flexibility of hematopoietic decisions and suggest that nurture can trump nature in dictating cDC differentiation.

On the subject of cDC ontogeny, we serendipitously found that mouse CDPs and pre-cDCs also express DNGR-1. Accordingly, when we genetically fate-mapped DNGR-1-expressing cells and their progeny, we were able to specifically label cDCs across all mouse tissues. Fate-mapping of cDC progenitors allows one to define cDCs on the basis of their haematopoietic origin rather than phenotype or function. An example of the utility of such an approach was provided by subsequent work examining the cells that develop in total mouse bone marrow cultures with GM-CSF, which have been used in many studies of cDC function. We were able to demonstrate that such cells are in fact heterogeneous and comprise both CDP-derived DCs and monocyte-derived macrophages. Our ongoing work on cDC ontogeny now aims to examine the development of cDC precursors in BM and the mode of tissue colonisation by blood-borne pre-DCs.