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, we showed that influenza and Sendai virus genomes constitute physiological ligands for RIG-I by virtue of the fact that they possess a 5' tri-phosphate (Cell 2010). Similarly, we argued that the negative strand of reovirus genomes also triggers RIG-I, this time through a 5' di-phosphate moiety (Nature 2014).

In cells infected with a picornavirus, we identified a physiological trigger for MDA5 that, surprisingly, turned out to be a short stretch of the antigenome (eLife 2014). In parallel, we have continued to study C-type lectin receptors (CLRs) that signal via Syk. We found that, like Dectin-1, Dectin-2 is a Syk-coupled pattern-recognition receptor for fungi (JEM 2009). We further uncovered an unexpected Syk-dependent role for DCs in orchestrating innate immunity to Candida albicans (PLOS Path 2014).

We have also focussed much effort on other Syk-coupled CLRs, namely CLEC-2 and DNGR-1. We found that CLEC-2 can be expressed by DCs (EJI 2011) and allows the stretching of fibroblastic reticular cells in T cell areas of lymph nodes following induction of inflammation (Nature 2014). DNGR-1 is expressed at high levels on mouse and human CD8α+ family DCs (JEM 2010, Blood 2012) where is constitutes a useful target for delivering antigens to those cells in vivo (EJI 2010). We further found that DNGR-1 is also expressed at lower levels by DC precursors in mouse and can be used to trace the progeny of those cells in fate-mapping models (Cell 2013). Notably, we identified DNGR-1 as a receptor for extracellular F-actin (Immunity 2012) and showed that is utilised by CD8α + DCs to detect dead cells and cross-present corpse-associated antigens to CD8+ T cells (Nature 2009, JCI 2012).

Our future plans involve continuing to work on validating the concept of cytoskeletal exposure as a sign of cell damage, further dissecting molecular pathways involved in DC activation, mapping DC heterogeneity and its functional implications across species, and trying to understand how signal integration by DC can regulate both immunity and tolerance to foreign or self antigens. It is anticipated that such studies will lead to the development of new strategies to target and activate or deactivate DC, thereby improving their use as tools for vaccination and immunotherapy in multiple clinical conditions.

Caetano Reis e Sousa

caetano@crick.ac.uk
+44 (0) 20 7269 2832

  • Qualifications and history
  • 1992 DPhil, University of Oxford, UK
  • 1993 Visiting Fellow, 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 Group Leader, the Francis Crick Institute, London, UK