Dendritic cells

Caetano Reis e Sousa : Past and current work

Intro page

Defence from infection requires identification of invading pathogens by immune mechanisms that distinguish self- from microbe-derived molecules. In addition, detection of tissue damage is important for discrimination between innocuous commensals and cytopathic pathogens, as well as for inducing immunity to tumours. The Immunobiology Laboratory studies the cellular and molecular processes by which viruses, fungi and dead cells are detected to trigger immune responses. It focuses in part on the study of dendritic cells (DCs), key immune sentinels sense infection and cancer to initiate immunity. Over the years, the Immunobiology Laboratory has found mechanisms used by the body to discriminate between viral and self RNA, uncovered a tyrosine kinase signalling pathway for microbial recognition, revealed that cytoskeletal exposure is a sign of cell damage that impacts immunity and helped unravel the complexity of DCs in host defence. 

In the last five years, the Immunobiology Laboratory's work has spanned several topics. On the subject of cell-intrinsic immunity to RNA viruses, the lab has shown that RIG-I, a cytosolic virus sensor, can detect 5' di-phosphate-bearing RNA like that 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 blocked by the effects of interferons, cytokines elicited by signals from RLRs or other innate immune receptors. This block is attributable in part to induction of a third RLR, LGP2, which acts as a negative regulator of antiviral RNA interference.

In a distinct line of investigation, the lab continued earlier 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 cDC1 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 presence of cytoskeletal proteins 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 cDC1s 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. This prostaglandin axis acts in part at the level of NK cells, which the lab found to be important players in the recruitment of cDC1s to tumours and initiation of anti-cancer immune responses.

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.

The lab's current 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, understanding DNGR-1 function 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.