C-type lectin receptors have recently been described as playing crucial roles in immunity and homeostasis since these proteins are able to recognize pathogens as well as self-Ags. We identified the C-type lectin-like receptor-1, CLEC-1, as being overexpressed in a model of rat allograft tolerance. We previously described in this model the expression of numerous cytoprotective molecules by graft endothelial cells and their interplay with regulatory CD4(+)CD25(+) T cells. In this study, we demonstrate that CLEC-1 is expressed by myeloid cells and specifically by endothelial cells in tolerated allografts and that CLEC-1 expression can be induced in endothelial cells by alloantigen-specific regulatory CD4(+)CD25(+) T cells. Analysis of CLEC-1 expression in naive rats demonstrates that CLEC-1 is highly expressed by myeloid cells and at a lower level by endothelial cells, and that its expression is down-regulated by inflammatory stimuli but increased by the immunoregulators IL-10 or TGFbeta. Interestingly, we demonstrate in vitro that inhibition of CLEC-1 expression in rat dendritic cells increases the subsequent differentiation of allogeneic Th17 T cells and decreases the regulatory Foxp3(+) T cell pool. Additionally, in chronically rejected allograft, the decreased expression of CLEC-1 is associated with a higher production of IL-17. Taken together, our data suggest that CLEC-1, expressed by myeloid cells and endothelial cells, is enhanced by regulatory mediators and moderates Th17 differentiation. Therefore, CLEC-1 may represent a new therapeutic agent to modulate the immune response in transplantation, autoimmunity, or cancer settings.