Caetano Reis e Sousa

Regulation of immunity by dendritic cells

The Immunobiology Laboratory studies the translation of innate into adaptive immunity by dendritic cells (DC). Activation of DC is a prerequisite for T cell priming and adaptive immunity. Activation can be driven by direct DC contact with potential pathogens or infected cells. This implies the existence of specific "pattern-recognition receptors" that allow DC to detect infection.

We and others have shown that one pathway for sensing infection by RNA viruses involves recognition of viral genomes or virally-infected cells in endosomal compartments and utilises members of the toll-like receptor (TLRs) family, including TLR9, 7, or 3. Viral genomes can additionally be recognised in the cytosol by helicases such as RIG-I, which are activated by RNAs bearing 5' tri-phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, some of these pathways are involved not only in direct sensing of pathogens but also in the recognition of perturbations that might accompany infection, such as cell death.

DC constitute a heterogeneous family and another major focus of the lab is on the role of different types of DC in the immune system. We have identified gene products that can be used to distinguish different murine DC subtypes, opening the door to selective manipulation of DC subsets in mouse models. In addition, we are characterising human equivalents of mouse DC subsets and examining their potential for immunotherapeutic intervention.

Suitable projects within these areas of research will depend on the interests of the successful candidate and will be defined upon discussion with the lab head and other lab members. The lab utilises a wide range of molecular and cellular techniques, including mouse genetic manipulation, flow cytometry, confocal microscopy, biochemistry, molecular biology. Opportunities exist for collaboration with other groups, at LRI and elsewhere.

References

1. Sancho D, Joffre O, Keller A, Rogers NC, Martinez D, Hernanz-Falcón P, Rosewell I and Reis e Sousa C. 2009. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 2009; 458: 899-903.
2. LeibundGut-Landmann S, Groß O, Robinson M, Osorio F, Slack E, Tsoni S, Schweighoffer E, Tybulewicz V, Brown G, Ruland J and Reis e Sousa C. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol 2007; 8: 630-638.
3. Pichlmair A, Schulz O, Tan C, Näslund T, Liljeström P, Weber F and Reis e Sousa C. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science 2006; 314: 997-1001.
4. Rogers N, Slack E, Edwards A, Nolte M, Schulz O, Schweighoffer E, Williams D, Gordon S, Tybulewicz V, Brown G and Reis e Sousa C. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 2005; 22: 507-517.
5. Diebold S, Kaisho T, Hemmi H, Akira S and Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303:1529-1531.