cDCs originate from precursors that develop in the bone marrow and give rise to pre-cDCs. Pre-cDCs then travel via the blood to colonise all tissues. In the absence of infection, we found that steady-state colonisation and subsequent cell division leads to groups of sister cDCs forming in tissues. But, upon respiratory virus infection, the steady-state trickle of pre-cDCs into the lung gives way to large scale influx of many pre-cDCs that accumulate specifically at the lung sites where the virus is replicating. We found that part of this is driven by a chemokine receptor known as CCR2 that helps pre-cDCs exit the bone marrow in greater numbers and migrate to the infected lung. CCR2 further directs the pre-cDCs to the foci of infection. Therefore, if we remove CCR2 from pre-cDC2s, we find many fewer cDCs at infection foci. This results in fewer cDCs activated by the virus migrating to lymph nodes to transmit information about the infection to T cells. We find that this results in a diminished T cell response to the virus that is insufficient to prevent re-infection.
In addition, we have examined how pre-cDC exit from bone marrow is regulated in the steady-state, i.e. in the absence of infection. We find that CXCR4, another chemokine receptor, acts to retain pre-cDCs in the bone marrow until they are “ready to leave”. Surprisingly. CXCR4 can be re-expressed by tissue-resident DCs in some instances, an observation that we made towards the end of the funding period. Finally, another receptor, DNGR-1, plays a subtle role in positioning the pre-cDCs appropriately within tissues such as the spleen.
Overall, the work performed under this project has provided key insights into how the cDC network is regulated in tissues, both in the steady-state and in situations of increased demand such as upon infection. The results from the project reveal an intricate interplay of chemokine signals that regulate pre-cDC exit from bone marrow and colonisation of tissues. They further reveal that acceleration of such exit is essential to sustain immune responses in tissues. As such, this project has markedly improved our understanding of cDC biology and the interface between innate and adaptive immunity. The results from the project have been amply disseminated through peer-reviewed publications, lectures and reviews.
