C-type lectin-like receptors (CTLRs) play critical roles in immunity and homeostasis by recognising a variety of microbial or endogenous ligands. Clecsf8 is a member of the Dectin-2 family of CTLRs. Clecsf8 shares important similarities with its relatives Mincle and Dectin-2, such as the lack of an integral signalling motif and a single, calcium dependent ligand binding domain. They were shown to associate with the FcRγ adaptor, which is essential for receptor surface expression and downstream signalling. Recent publications revealed an important role for Clecsf8 in anti-mycobacterial immunity. It was reported to recognise the mycobacterial cord factor (TDM), similar to the related CTLR Mincle, as well as a possible role in candidiasis. In this study, we characterised the underlying mechanism of Clecsf8 expression in a context of mycobacterial disease. The generation of novel anti-Clecsf8 monoclonal antibodies allowed us to characterise the expression of Clecsf8 in detail in homeostasis and inflammation in murine models in vivo and culture systems in vitro. We found Clecsf8 to be predominantly expressed on monocytes/macrophages and neutrophils within e. g. the peritoneal cavity, blood and bone marrow. Notably, Clecsf8 was expressed only weakly in the lung, but strongly upregulated in a pulmonary mycobacterial infection model. In vitro, Clecsf8 expression on elicited macrophages was strongly induced upon treatment with microbial stimuli in a Myd88- and Mincle dependent manner. Interestingly, surface expression of Clecsf8 in a murine fibroblast cell line was greatly enhanced by co-transfection of Mincle, but not another related CTLR, Dectin-2. Notably, we confirmed mycobacteria as a ligand of CLECSF8, but found no role for the receptor in Candida immunity. In conclusion, Clecsf8 is a myeloid expressed, mycobacterial receptor, showing significant interdependence with Mincle and is regulated through the Myd88 pathway.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:698845 |
| Date | January 2016 |
| Creators | Kerscher, Berhard Gerhard Richard |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230779 |
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