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 Activation

Abstract

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.

Cell-surface C-type lectin-like receptor CLEC-1 dampens dendritic cell activation and downstream Th17 responses

“…Almost all cultured moDCs express cell-surface CLEC-1, which is largely coexpressed with the other CLR DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN); however, in contrast to blood, CLEC-1 does not appear to be restricted to the CD16 2 subpopulation (Figure 1Ci-ii). Importantly, as we previously described in rats, 4 CLEC-1 expression is decreased on human moDCs by inflammatory stimuli such as toll-like receptor (TLR) ligands, and is upregulated by TGF-b (Figure 1Ciii-iv). By IHC, we confirmed that CLEC-1 expression is mostly intracellular for ECs, and at the cellsurface for moDCs and monocytes (Figure 1Di-ii).…”

“…4,5,8 qRT-PCR analysis in pooled organs demonstrates a strong expression of CLEC1A transcripts in placenta and lung, and a more moderate expression in the lymphoid organs including spleen, LNs, thymus, and tonsils (supplemental Figure 4i). In human cell subtypes, abundant CLEC1A transcripts were found in neutrophils, monocytes, moDCs, and HAECs (supplemental Figure 4ii).…”

“…3 We previously identified the CTLR, C-type lectin-like receptor-1 (CLEC-1), to be upregulated in a heart allograft model of tolerance in rats. 4 We demonstrated that CLEC-1 is expressed by rat myeloid and endothelial cells (ECs), and is downregulated by pro-inflammatory stimuli and enhanced by transforming growth factor b (TGF-b). Moreover, our in vitro studies demonstrated that CLEC-1 inhibition in rat DCs via RNA interference enhanced subsequent DC-mediated CD4 1 T helper 17 (Th17) activation.…”

“…Moreover, our in vitro studies demonstrated that CLEC-1 inhibition in rat DCs via RNA interference enhanced subsequent DC-mediated CD4 1 T helper 17 (Th17) activation. 4 CLEC-1 belongs to the DCassociated C-type lectin-1 (DECTIN-1) cluster of CTLRs, and although identified a long time ago, 5,6 corresponding exogenous and endogenous ligands are unknown and downstream signaling remains uncharacterized. CLEC-1 does not contain an immunoreceptor tyrosine-based activation or inhibitory motif in the cytoplasmic tail, but rather a tyrosine residue in a noncharacterized signaling sequence [YSST], in addition to a tri-acidic motif [DDD].…”

Lectin-like Receptor Ly49s3 on Dendritic Cells Contributes to the Differentiation of Regulatory T Cells in the Rat Thymus

“…In humans, other lectin-like receptors may replace the function of Ly49 family proteins. In this regard, DECTIN-1 and CLEC-1, expressed in DCs, have been demonstrated to be involved in the fate determination of T cells between Tregs and Th17 cells (28)(29)(30). Lectin-like receptors seem to be more widely involved in the regulation of DC functions than was previously supposed.…”