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Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis

Final Report Summary - CLR SENSING NECROSIS (Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis)

Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity. Moreover, these tissue-damage induced signals can combine with signals from microbes during infection or from the microbiota to initiate and shape immunity and inflammation. The CLR Sensing necrosis proposal aimed to investigate the role of myeloid C-type lectin receptors sensing necrosis in the initiation and modulation of immunity and inflammation.

We have investigated how myeloid cells sense and decode information from tissue damage and microbes. We found that the DC-specific CLR that detects necrosis DNGR-1 (Clec9a) decodes for the immunogenicity of the necrotic cell-associated cargo, whereas other pattern recognition receptors decode for the adjuvanticity (Iborra et al. J. Clin. Invest. 2012). This research shows for the first time a division of labor between sensors of tissue-damage and pathogen-associated molecular patterns. Moreover, when examining downstream effectors of the CLR Dectin-1, we found that SHIP-1 phosphatase modulates the signalling via Dectin-1 by counterbalancing the Syk-PI3K mediated generation of phosphoinositides (Blanco Menéndez et al. J. Immunol. 2015). This research shows how is the fine regulation of ROS production downstream sensing microbes by Dectin-1. We also found that the trypanosomatid Leishmania secretes a soluble ligand detected by the CLR Mincle that triggers association to SHP-1 and inhibits DC activation (Iborra, Martínez-López et al. Immunity. 2016b). This work is the first example of an inhibitory ITAM pathway downstream a pattern recognition receptor. Finally, we have additionally explored new avenues connecting sensing of live signatures of bacteria with the generation of mitochondrial adaptations that affect electron flow in the electron transport chain (Garaude et al. Nat. Immunol. 2016).

Our research on the specific function of conventional DC subsets sensing tissue damage and microbes led us to establish the subset of conventional DCs type 1 (cDC1) as main generators of IL-12 that is essential for generation and maintenance of Th1 immunity in the tissue following Leishmania infection (Martínez-López et al. Eur. J. Immunol. 2015). This DC subset is also crucial for the generation of a basal anti-tumour T cell response that can be boosted by using immuno-modulatory antibodies (Sánchez-Paulete et al. Cancer Discov. 2016). In addition, specific signals provided by cDC1 and dependent on crosspriming by DGNR-1 are required for optimal generation of tissue-resident but not circulating memory T cells during viral infection (Iborra et al. Immunity. 2016a). These results are potentially relevant for vaccination and we are currently exploring avenues for novel immunotherapy strategies based on DC targeting.