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Innate immunity and dendritic cells

  • Full or part time
    Dr C Reis e Sousa
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Caetano Reis e Sousa’s Group based at the Francis Crick Institute (the Crick).

Research in the Immunobiology Laboratory is centred on the receptors and signalling pathways that detect infection, injury and cancer. We have shown that RNA viruses and virally-infected dead cells can be detected by members of the toll-like receptor (TLRs) family, including TLR7 and 3, after endocytosis by specialised sensor cells. We have additionally shown that viruses can be recognised in all cells via cytosolic receptors such as RIG-I, which is activated by viral RNA genomes bearing 5’ tri- or di-phosphates. Finally, we have identified a distinct pathway for immunity to fungi mediated by C-type lectin receptors, which signal via Syk kinase in phagocytes. Notably, our work has also shown that the C-type lectin/Syk pathway is additionally involved in recognition of cell death. For example, one Syk-coupled C-type lectin, DNGR-1, binds to F-actin exposed by dead cells and signals to modulate immunity to cytopathic pathogens and, possibly, cancer. The notion that cytoskeletal exposure is a sign of tissue damage forms the basis of another line of investigation to understand how cytoskeletal components spilling into the extracellular space trigger responses in fruit flies and mammals.

Investigation into receptors and signalling pathways goes hand in hand with research into the cells that carry out innate immune detection. These cells include dendritic cells (DCs) and one focus of the lab is on defining DC subtypes and their role. We have identified gene products that can be used to mark DC progenitors or to distinguish different murine DC subtypes, opening the door to selective manipulation of DC and/or DC subsets in mouse models. In addition, we are characterising the human equivalents of defined mouse DC subsets and examining their potential as targets for immunotherapeutic intervention. Finally, we study the role of DCs in immunity to cancer and examining how tumours subvert DCs for immune escape. Collectively, the work of the Immunobiology Laboratory helps build a global picture of the cells, receptors and signalling pathways that regulate immunity and have applications in immunotherapy of cancer and infectious diseases.

Only one studentship is available with our group. The precise project will be defined upon discussion with the supervisor. It is likely to centre on new efforts in the lab to understand the signals that regulate DCpoiesis and that could be harnessed to increase immunity.

Candidate background
This studentship is suitable for any candidate with a strong background in biology and experience of working in a research laboratory and of analysing data. The student will receive training in how to formulate scientific questions and design experimental strategies to rigorously address them. In addition, training in data interpretation, data presentation and scientific discourse skills will be provided. The lab utilises a wide variety of molecular and cellular techniques, including animal manipulation, flow cytometry, confocal and intravital microscopy, biochemistry, genetics and molecular biology. Opportunities exist for collaboration with other groups, at Crick and elsewhere.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

References
1. Cabeza-Cabrerizo, M., van Blijswijk, J., Wienert, S., Heim, D., Jenkins, R. P., Chakravarty, P., . . . Reis e Sousa, C. (2019)

Tissue clonality of dendritic cell subsets and emergency DCpoiesis revealed by multicolor fate mapping of DC progenitors.

Science Immunology 4: eaaw1941. PubMed abstract

2. Schulz, O., Hanč, P., Böttcher, J. P., Hoogeboom, R., Diebold, S. S., Tolar, P. and Reis e Sousa, C. (2018)

Myosin II synergizes with F-actin to promote DNGR-1-dependent cross-presentation of dead cell-associated antigens.

Cell Reports 24: 419-428. PubMed abstract

3. Böttcher, J. P., Bonavita, E., Chakravarty, P., Blees, H., Cabeza-Cabrerizo, M., Sammicheli, S., . . . Reis e Sousa, C. (2018)

NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control.

Cell 172: 1022-1037 e1014. PubMed abstract

4. Helft, J., Anjos-Afonso, F., van der Veen, A. G., Chakravarty, P., Bonnet, D. and Reis e Sousa, C. (2017)

Dendritic cell lineage potential in human early hematopoietic progenitors.

Cell Reports 20: 529-537. PubMed abstract

5. Hanč, P., Fujii, T., Iborra, S., Yamada, Y., Huotari, J., Schulz, O., . . . Reis e Sousa, C. (2015)

Structure of the complex of F-actin and DNGR-1, a C-type lectin receptor involved in dendritic cell cross-presentation of dead cell-associated antigens.

Immunity 42: 839-849. PubMed abstract

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