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The C-Type Lectin-Like Receptor CLEC-1, Expressed by Myeloid Cells and Endothelial Cells, Is Up-Regulated by Immunoregulatory Mediators and Moderates T Cell Activation¹

INSERM, Unité 643, Nantes, France; Institut de Transplantation et de Recherche en Transplantation, Centre Hospitalier Universitaire de Nantes, Nantes, France; and Faculté de Médecine, Université de Nantes, Nantes, France

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 TGFβ. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Fondation pour la Recherche Médicale, the Fondation CENTAURE, and from Vaincre la Mucoviscidose. P. Thebault was supported by the Société Francophone de Transplantation, the Fondation Progreffe, and by the Fondation des Treilles.

² Address correspondence and reprint requeststo Dr. Elise Chiffoleau, INSERM, Unité 643, Centre Hospitalier Universitaire de Hôtel-Dieu, 30 boulevard Jean Monnet, 44093 Nantes, France. E-mail address: Elise.Chiffoleau{at}univ-nantes.fr

³ Abbreviations used in this paper: EC, endothelial cell; AU, arbitrary unit; BMDC, bone marrow-derived dendritic cell; CLEC-1, C-type lectin-like receptor-1; DAPI, 4',6-diamidino-2-phenylindole; DC, dendritic cell; DST, donor-specific transfusion; HAEC, human aortic endothelial cell; HPRT, hypoxanthine phosphoribosyltransferase; RNAi, RNA interference.