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

Abstract

Key Points• CLEC-1 is restricted to CD16 2 myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation.• CLEC-1-deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell priming and effector Th responses.Dendritic cells (DCs) represent essential antigen-presenting cells that are critical for linking innate and adaptive immunity, and influencing T-cell responses. Among pattern recognition receptors, DCs express C-type lectin receptors triggered by both exogenous and endogenous ligands, therefore dictating pathogen response, and also shaping T-cell immunity.We previously described in rat, the expression of the orphan C-type lectin-like receptor-1 (CLEC- 1) by DCs and demonstrated in vitro its inhibitory role in downstream T helper 17 (Th17)activation. In this study, we examined the expression and functionality of CLEC-1 in human DCs, and show a cell-surface expression on the CD16 2 subpopulation of blood DCs and on monocytederived DCs (moDCs). CLEC-1 expression on moDCs is downregulated by inflammatory stimuli and enhanced by transforming growth factor b. Moreover, we demonstrate that CLEC-1 is a functional receptor on human moDCs and that although not modulating the spleen tyrosine kinase-dependent canonical nuclear factor-kB pathway, represses subsequent Th17 responses.Interestingly, a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and is associated with a higher level of interleukin 17A (IL17A). Importantly, using CLEC-1-deficient rats, we showed that disruption of CLEC-1 signaling led to an enhanced Il12p40 subunit expression in DCs, and to an exacerbation of downstream in vitro and in vivo CD4 1 Th1 and Th17 responses. Collectively, our results establish a role for CLEC-1 as an inhibitory receptor in DCs able to dampen activation and downstream effector Th responses. As a cell-surface receptor, CLEC-1 may represent a useful therapeutic target for modulating T-cell immune responses in a clinical setting.

C-Type Lectin-Like Receptors As Emerging Orchestrators of Sterile Inflammation Represent Potential Therapeutic Targets

“…This cross talk is regulated by the level and localization of their expression, by their interaction and by their collaborative or conflicting signaling ( 6 , 7 ). To date, CTLRs “Dectin” families were best known for their involvement in host defense as referred in these excellent reviews ( 1 – 4 , 8 , 9 ). However, over recent years, these receptors have gained growing interest for their ability to respond also to a wide variety of endogenous ligands (Figure 1 ).…”

C‐type lectin receptors of the Dectin‐1 cluster: Physiological roles and involvement in disease

“…MelLec has also been implicated in modulating T cell function . In rats, the absence of MelLec led to exacerbated Th17 responses, which correlated with enhanced IL‐12p40 expression by DCs . Notably, decreased MelLec expression in human lung transplants was associated with increased levels of IL‐17A and chronic rejection .…”

“…Melanin sensing C‐type Lectin receptor (MelLec, CLEC‐1, CLEC‐1A) was identified nearly two decades ago and is broadly expressed by endothelial cells in humans, mice, and rats. In humans and rats, this receptor is also expressed on myeloid cells, including various DC populations, monocytes, macrophages, and granulocytes . MelLec was recently shown to recognise 1, 8‐dihydroxynaphthalene melanin, an immunologically active component found in the cell wall of melanised fungi, such as Aspergillus fumigatus .…”

“…MelLec has also been implicated in modulating T cell function . In rats, the absence of MelLec led to exacerbated Th17 responses, which correlated with enhanced IL‐12p40 expression by DCs .…”

“…Similar findings were also observed in rat allograft models. This suggests that MelLec may play a role in the tolerogenic response to allografts, through recognition of an unknown endogenous ligand . How MelLec mediates its physiological functions is still unknown, although the receptor contains a YSST and tri‐acidic DDD motif in its cytoplasmic tail that could potentially mediate intracellular signalling (Fig.…”