Caetano Reis e Sousa: Projects

Regulation of immunity by dendritic cells and innate mechanisms involved in sensing pathogen presence and tissue damage.

In the recent past, the Immunobiology Laboratory continued earlier work on cell-intrinsic immunity to RNA viruses to show that RIG-I, a cytosolic virus sensor, can detect 5' di-phosphate-bearing RNA, such as present in the genome of reoviruses. In addition, the lab isolated an RNA agonist for MDA5, a RIG-I-like receptor (RLR), from cells infected with a picornavirus. Finally, the lab found that antiviral RNA interference, an ancestral form of antiviral defence, is preserved in vertebrates but masked by the effects of interferons, cytokines elicited by signals from RLRs or other innate immune receptors. In a distinct line of investigation, the lab continued its studies of myeloid C-type lectin receptors that signal via Syk. The lab found that provision of one of these, CLEC-2, by DCs at the outset of an immune response causes relaxation of certain lymph node stromal cells permitting expansion of the organ. A distinct Syk-coupled C-type lectin receptor, DNGR-1, was previously found by the lab to be used by the DC1 subset of DCs to detect F-actin exposed by cells undergoing necrosis. This suggested that extracellular recognition of cytoskeletal components is an evolutionarily-ancient means of detecting tissue damage. Consistent with that notion, the lab recently found that extracellular actin elicits a response in Drosophila melanogaster akin to tissue injury. To further understand the role of extracellular actin recognition, the lab solved the structure of the DNGR-1/F-actin complex and validated the importance of F-actin detection and a pH-induced conformational change in DNGR-1 in allowing DC1s to extract antigens from cell corpses for presentation to CD8+ T cells. This process can contribute to immunity to cytopathic viruses and to cancer and, in the context of the latter, the lab found that DC activation and immune control can be subverted by prostaglandin E2 produced by tumour cells. Independently of its presence and function in differentiated DCs, DNGR-1 was additionally found by the lab to be also expressed by mouse DC precursors and was used to fate-map those cells in vivo. In an extension of the latter work, the lab demonstrated that supposedly-pure "DC" cultures widely-used for mouse immunology research contain a mixture of cells of distinct origins, some of which are better classified as macrophages (MØs).

The lab's future plans involve continuing to work on validating the concept of cytoskeletal exposure as a sign of cell damage, further dissecting molecular pathways involved antiviral innate immunity, understanding DC development, mapping DC heterogeneity and its functional implications across species, and investigating how DCs detect tumours and initiate anticancer immunity. It is anticipated that such studies will lead to a greater understanding of immune homeostatic mechanisms and the development of new strategies for vaccination and immunotherapy in multiple clinical conditions.

Reis e Sousa Caetano

Caetano Reis e Sousa

caetano@crick.ac.uk
+44 (0)20 379 61310

  • Qualifications and history
  • 1992 DPhil, University of Oxford, UK
  • 1993 Postdoc, National Institute of Allergy and Infectious Diseases, National Institute of Health, USA
  • 1998 Established lab at the Imperial Cancer Research Fund, UK (in 2002 the Imperial Cancer Research Fund became Cancer Research UK)
  • 2015 Senior Group Leader, the Francis Crick Institute, London, UK