Impaired clearance of apoptotic cells results in the accumulation of secondary necrotic corpses, with profound immune consequences. Cell death triggers the macrophage inflammatory response, which normally contributes to tissue repair but under certain conditions can induce a state of chronic inflammation that is the basis of many diseases. Necrotic cells can also provoke an adaptive immune response via presentation of antigens by dendritic cells (DCs), and necrosis might explain adaptive immunity in seemingly infection-free situations, such as autoimmunity or spontaneous or therapy-induced tumour rejection. Myeloid C-type lectin receptors (CLRs), such as Mincle in macrophages and CLEC9A (DNGR-1) in DCs, have been identified as receptors for necrotic cells that couple to the tyrosine kinase Syk, which in turn can trigger innate and adaptive immune responses.
Our hypothesis is that recognition of cell death by Syk-coupled CLRs in myeloid cells might lie at the root of immune pathologies associated with an accumulation of dead cells. Our research program falls into three main strands. First, we are characterizing signaling and gene induction via CLEC9A as a model of innate sensing of necrotic cells by DCs. Second, we are investigating the role of Syk signaling and Syk-coupled receptors in myeloid cells in models of autoimmunity and of immune responses to dead tumor cells following a chemotherapy treatment. CLEC9A and Mincle are prime candidate mediators of the response to dead cells in DCs and macrophages, but our preliminary findings indicate that Syk deficiency has a more profound effect than CLEC9A deficiency on the sensing of necrosis by DCs, suggesting that additional receptors are involved. The third strand of our research is thus focused on the identification of new Syk-coupled receptors that recognize necrosis in myeloid cells.
David Sancho graduated in Biology at the University of Murcia, Spain (1995) and pursued a research career while specializing in Immunology through the Spanish National Health System program at the Hospital de la Princesa, Madrid (2000). The subject of his PhD thesis (Universidad Autónoma de Madrid, 2003) was the function of the C-type lectin CD69, with special emphasis on models of inflammation. During his postdoc tenure at the London Research Institute, (Cancer Research UK, 2004-2009) he discovered a new C-type lectin receptor specific to dendritic cells (CLEC9A, DNGR-1) that was subsequently used for targeted anti-tumor vaccination. Through the generation of CLEC9A deficient mice, he found that this receptor is involved in the generation of immunity associated with dead cells. This work has possible implications in the origins of chronic inflammation and autoimmunity. He joined the CNIC in September 2009.