Periodic Reporting for period 4 - DCPOIESIS (Steady-state and demand-driven dendritic cell generation)
Período documentado: 2023-03-01 hasta 2025-02-28
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 and it is not known how their low numbers are controlled and whether they are sufficient to elicit immunity
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.
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.
This project has markedly improved our understanding of cDC biology and the interface between innate and adaptive immunity. Our studies have provided support for the concept of emergency cDCpoiesis and showed that it is regulated in part by chemokine receptor signalling in pre-cDCs, which orchestrates bone marrow exit, directed migration and tissue seeding. While the project has now ended, there is still ongoing work to further understand how cDCpoiesis is regulated at the steady-state and in “emergency” conditions. Notably, we are finalising a study on emergency cDCpoiesis in response to intramuscular vaccination. We are also analysing how it may impact anti-tumour immunity. These and other follow-up studies build on the achievements of the project and allow for continuation of this line of investigation, with potential applications for immunotherapy and vaccination.