Caetano Reis e Sousa

 

Innate immunity and dendritic cells

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 tumoiurs 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 within these broad areas of research will depend on the interests of the successful candidate and will be defined upon discussion with the supervisor.

1. Srinivasan, N., Gordon, O., Ahrens, S., Franz, A., Deddouche, S., Chakravarty, P., Phillips, D., Yunus, A. A., Rosen, M. K., Valente, R. S., Teixeira, L., Thompson, B., Dionne, M. S., Wood, W. and Reis e Sousa, C. (2016)
Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster.
eLife  5: e19662. PubMed abstract

2. Zelenay, S., van der Veen, A. G., Böttcher, J. P., Snelgrove, K. J., Rogers, N., Acton, S. E., Chakravarty, P., Girotti, M. R., Marais, R., Quezada, S. A., Sahai, E. and Reis e Sousa, C. (2015)
Cyclooxygenase-dependent tumor growth through evasion of immunity.
Cell  162: 1257-1270.PubMed abstract

3. Hanč, P., Fujii, T., Iborra, S., Yamada, Y., Huotari, J., Schulz, O., Ahrens, S., Kjær, S., Way, M., Sancho, D., Namba, K. and 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

4. Acton, S. E., Farrugia, A. J., Astarita, J. L., Mourão-Sá, D., Jenkins, R. P., Nye, E., Hooper, S., van Blijswijk, J., Rogers, N. C., Snelgrove, K. J., Rosewell, I., Moita, L. F., Stamp, G., Turley, S. J., Sahai, E. and Reis e Sousa, C. (2014)
Dendritic cells control fibroblastic reticular network tension and lymph node expansion.
Nature 514: 498-502. PubMed abstract

5. Schraml, B. U., van Blijswijk, J., Zelenay, S., Whitney, P. G., Filby, A., Acton, S. E., Rogers, N. C., Moncaut, N., Carvajal, J. J. and Reis e Sousa, C. (2013)
Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage.
Cell  154: 843-858. PubMed abstract