Cabeza Cabrerizo, Maria del Mar; (2019) Establishment and remodelling of the dendritic cell network in tissues. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Conventional dendritic cells (cDCs) are leucocytes that act as sentinel cells, sensing the extracellular environment and initiating immune responses against infection and cancer. cDCs develop from a common progenitor in the bone marrow (BM) that travels via the blood in the form of a pre-cDC to seed tissues. How pre-cDCs colonise different organs, whether this is affected by infection and how BM production is matched to cDC demand in the periphery remains poorly understood. During my PhD I used a mouse model for multicolour fate mapping of cDC progenitors and found that many pre-cDCs and cDCs divide in tissues generating single cDC clones. Upon infection with influenza A virus, lung cDCs increase in number due to accelerated CCR2-dependent recruitment of pre-cDCs from the BM rather than local proliferation, diluting pre-existing clones. This recruitment generates new waves of cDCs in the lung that seem to be necessary for inducing antiviral immunity. Preliminary results using a reporter mouse for DC progenitors show that more cells localise close to BM sinusoids during infection, possibly to favour the rapid release of pre-cDCs into the blood circulation. Interestingly, cancer and vaccine adjuvants also mobilise BM cDC progenitors, demonstrating that this is probably a conserved mechanism by which the cDC network adapts to different challenges. In addition, pre-cDCs can directly sense pathogen-associated molecular patterns via toll-like receptors, which might be necessary for the progenitors to respond to infection or tissue damage. In sum, my results provide evidence for a tightly regulated cDC network that is often organised in clones. However, when a bigger arsenal of cDCs is required, the BM responds by pumping out more pre-cDCs, which is a new component of immunity to infection. More studies might reveal whether CCR2 also drive this phenomenon during cancer and the mechanism underlying pre-cDC exit from the BM.

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