Skip to main content

Steady-state and demand-driven dendritic cell generation

Periodic Reporting for period 2 - DCPOIESIS (Steady-state and demand-driven dendritic cell generation)

Reporting period: 2020-03-01 to 2021-08-31

Conventional dendritic cells (cDCs) are white blood cells found in all tissues of mice and humans. Upon infection or cancer development, cDCs become activated and migrate to specialised organs known as lymph nodes where they transmit information about the pathogen or tumour to other white blood cells known as T and B cells. T and B cells mount a protective immune response and depend entirely on the alert signals they get from the cDC sentinels. However, there are very few cDCs in tissues at any given time. It is not known how their numbers are controlled and whether their low numbers are sufficient to elicit immunity. In this project, we aim to understand how the body regulates the generation of cDCs and their tissue colonisation in order to ensure immunity.
We found that infection with influenza A virus causes a rapid increase in the number of cDCs in the lungs of mice. All cDCs originate from precursors, which, like for all other white blood cells, develop in the bone marrow and then travel via the blood as pre-cDCs 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 influenza A 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 because, when we remove CCR2 from pre-cDCs, they can still colonise the lung normally in the absence of infection but lose the ability to home to virus-containing lung sites in influenza A virus-infected mice. As a consequence, there are fewer cDCs at infection foci to be activated by the virus and to migrate 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 other words, the results from our project thus-far tell us that the generation of cDCs is elastic and responsive to demand and show that pre-cDC “backup” from bone marrow is essential to sustain an immune response against a respiratory virus.
Ongoing work aims to understand how the information about infection is communicated from lungs to bone marrow to allow greater efflux of pre-cDCs into blood (which we find also happens upon influenza A virus infection but is independent from CCR2). We are also trying to understand if “emergency” cDC tissue colonisation is important for immunity to cancer and parasites, in addition to influenza A virus. Finally, all these questions require us to understand where exactly in the bone marrow pre-cDCs develop and how they then exit into blood in the steady state and upon increased demand. We are studying all these issues in mice using the power of mouse genetics to engineer animals in which we can visualise cDCs and their precursors, as well as manipulate their properties. We hope that understanding the mechanisms that regulate pre-cDC development in bone marrow and subsequent seeding of tissues via blood in normal and “emergency” situations may allow us to manipulate the immune system to increase responses to infectious agents, cancers and vaccines.
Grant structure and objectives