Development and Plasticity of murine plasmacytoid dendritic cells
The data presented in this thesis identifies a subpopulation of CCR9- MHC class IIlow BST2+ Siglec H+ plasmacytoid dendritic cells (pDCs) within the bone marrow (BM) pDC population. CCR9- MHC class IIlow BST2+ Siglec H+ pDCs express the essential pDC transcription factor E2-2 and produce high levels...
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|The data presented in this thesis identifies a subpopulation of CCR9- MHC class IIlow BST2+ Siglec H+ plasmacytoid dendritic cells (pDCs) within the bone marrow (BM) pDC population. CCR9- MHC class IIlow BST2+ Siglec H+ pDCs express the essential pDC transcription factor E2-2 and produce high levels of interferon-α (IFN-α) and proinflammatory cytokines upon toll-like receptor 9 (TLR9) stimulation. This phenotypically immature pDC population is an immediate precursor for fully differentiated CCR9+ pDCs in vitro as well as in vivo, but does not harbour a pDC-specific gene rearrangement in the Ig gene locus.
CCR9- pDCs retain plasticity to downregulate pDC specific surface molecules and upregulate CD11b and MHC class II, acquiring phenotype and function of CD8α- CD11b+ conventional dendritic cell (cDC) - like cells after conditioning with supernatant derived from colonic epithelial cells or exposure to recombinant granulocyte macrophage colony stimulating factor (GM-CSF) in vitro. Functionally cDC-like cells generated from CCR9- pDCs acquire properties of cDCs such as efficient T cell activation and the production of high levels of proinflammatory cytokines comparable to those of splenic CD8α- DCs. This phenotypic and functional change is also reflected on the level of transcription factor expression by downregulation of E2-2, Spi-b and IRF8 but upregulation of ID2, PU.1 and BATF3.
CCR9- pDCs can give rise to fully differentiated CCR9+ pDCs and CD11b+ MHC class IIhigh cDC-like cells locally in the tissue in vivo in the steady state. However the plasticity and lineage commitment of CCR9- pDCs is regulated in a tissue specific manner. In BM and liver CCR9- pDCs primarily give rise to CCR9+ pDCs, whereas in spleen, lymph nodes, lung and small intestine a substantial fraction deviates from the pDC lineage to the cDC lineage.
Furthermore, this study shows that GM-CSF is necessary for the appearance of CCR9- pDCs and CCR9+ pDCs in lung and small intestine but is dispensable for the generation of CD11b+ MHC class IIhigh cDCs from CCR9- pDCs in vivo. Moreover, GM-CSF controls the proliferation of CCR9- and CCR9+ pDCs in BM and spleen upon adoptive transfer.
In conclusion these results show that CCR9- pDCs are tissue resident precursors of pDCs and cDCs and that the generation of DC subsets is regulated by tissue derived factors, thereby allowing adaptation to local microenvironments. This increases the flexibility of the DC compartment under circumstances of infection or inflammation.