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Where it all begins: exploring Dendritic cell control of viral infection and cell development in the bone marrow
thesisposted on 22.02.2017, 02:21 by Fancke, Benjamin Richard
The bone marrow (BM) is considered the birthplace of haematopoiesis. It consists of specialised microenvironments involved in the survival and development of precursor cells and the guidance of haematopoiesis. More recently the BM has been implicated as a potential site for the initiation of primary immune responses against pathogens. Such immune responses within the BM have the potential to affect the development of hematopoietic lineages therein. However, the accessory cells potentially capable of promoting immune responses within the BM, such as dendritic cells (DC), have been only crudely characterised. Here we identify all DC populations of mouse BM and discover DC subsets that express comparable levels of MHCII and co-stimulatory markers to mature DC of the spleen. These mature, BM resident DC produce pro-inflammatory cytokines and chemokines but in the steady-state appear potentially tolerogenic with relatively poor ability to stimulate naïve T cells. While plasmacytoid (p)DC are known to mature in the BM, conventional (c)DC are thought to migrate from the BM as pre-cDC to mature in peripheral organs. As well as DC of mature phenotype, the BM also contains immature DC that are subset committed and express MHCII, but are phenotypically and functionally underdeveloped compared to DC found in peripheral lymphoid organs. Our identification of several stages of cDC development within the BM implicates it as an organ where DC can mature in entirety without the need to access peripheral organs for final stages of maturation. Lymphocytic choriomeningitis virus (LCMV) is a BM tropic virus. We investigated the behaviour of BM DC during LCMV infection. DC numbers in the BM are increased during the acute and then chronic phases of infection. Acute DC increases are attributable to enhanced development of immature and pre-DC within the BM in response to endogenous, inflammation induced fms-related tyrosine kinase 3 ligand (FL). Interestingly, BM DC developing to maturity under conditions of increased FL show enhanced antigen presenting cell functions. Furthermore, during chronic stage LCMV infection the most mature DC subset of the BM, present in very low numbers during steady-state, is remarkably increased within the BM. It thus appears the BM plays varying roles supporting these novel DC subsets during acute and chronic phases of infection. Our findings implicate BM DC as regulators of cellular homeostasis during steady-state conditions that can rapidly respond to viral infection by increasing in number and antigen presentation potency. Such responses reveal the BM microenvironment to be a site for the rapid development of “emergency”, inflammation induced DC that likely re-seed DC populations of peripheral organs during infection, but also as a site for the accumulation of mature DC potentially capable of initiating immune responses therein. Our elucidation of these mature and precursor DC within the BM identifies novel cellular targets for clinical manipulation of immune responses.