Fungal infections are a global threat, causing over 1.5 million deaths globally each year. Effective immunity from both innate and adaptive immune systems is essential for protection. Dendritic cells (DCs) are the bridge between innate and adaptive immune systems. They recognise fungal pathogens through C-type lectin receptors (CLRs), such as Dectin-1, then migrate to draining lymph nodes where they present antigen to T cells. The second signal required for successful T cell activation is from co-signalling molecules that are critical in shaping the T cell response. Loss of Dectin-1 on DCs during systemic Candida albicans infection in mice leads to increased fungal burden, and reduced CD4+ T cell activation and proliferation in the gut. The molecules on DCs that are involved in this aberrant T cell response were explored in this study. Using microarray and quantitative polymerase chain reaction analysis, a novel class of CLRs, were identified as downregulated on DCs from Dectin-1 knockout mice compared to wildtype mice. Furthermore, addition of Fc-CLR fusion proteins during in vitro T cell activation assays, showed that these CLRs have profound effects in modulating T cell activation. Additionally, the ligand for these CLRs was identified on all T helper cell subsets, including Th1, Th2, Th17 and Treg. Ligand expression was also identified on various cell types including epithelial cells, endothelial cells, stromal cells, CD4+ T cells and CD8+ T cells from multiple tissues including the gut, liver, pancreas, and lung, in both naïve and inflammatory conditions. Suggesting a broader role for these receptors in modulating the immune response. Finally, several methods were optimised to identify unknown ligands for these CLRs. Together these findings represent the novel discovery of CLRs as DC receptors, and their impact on T cells supports the identification of a novel class of co-signalling molecules. This has huge implications for development of therapeutics and vaccines for fungal infections and beyond.Medical Research Council (MRC)