CLRs are also referred to as calcium-dependent (C-type) lectins, and are a part of the lectin superfamily. They comprise carbohydrate-binding C-type lectin domains. CLRs are predominantly transmembrane, and are primarily expressed by DCs, macrophages, and monocytes. Carbohydrate recognition domains (CRDs) enable the CLRs to identify glycan structures on the external surface of pathogens (van Kooyk & Rabinovich, 2008). CLRs are capable of identifying a variety of PAMPs, and stimulating a broad-spectrum of signals that lead to immune responses tailored to specific pathogen attacks. They also recognize diverse endogenous (self-) ligands that regulate homeostasis, including glycans on the surface of tumor cells (Dambuza & Brown, 2015).

CLRs can be categorized into two groups based on their signaling potential. One group contains immunological-receptor tyrosine-based activating motifs (ITAMs) in their integrin cytoplasmic tails, including mannose receptor (MR) and DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), described in the next subsection. The ITAM domains engage with Syk family kinases, leading to the creation of the Card9/Bcl10/ Malt1 complex that activates the NF-κB pathway, and other cellular immune responses. Some activating CLRs interact with an ITAM-containing adaptor protein, Fc Receptor gamma chain (FcRγ). The second group possesses immune receptor tyrosine-based inhibitory motifs (ITIMs) that impede the activation of immune cells responses, thereby regulating immune responses (Chiffoleau, 2018).

On the basis of their molecular structure, CLRs may be subgrouped into type I transmembrane proteins, type II transmembrane proteins, and soluble CLRs. Macrophage MR and DEC-205 are type I transmembrane CLRs, which have multiple CRDs or CRD-like domains. Type II transmembrane CLRs are Dectin-1, Dectin-2, DC-SIGN, DC NK lectin group receptor-1 (DNGR-1), and macrophage-inducible C-type lectin (Mincle). Mannose binding lectin is a soluble CLR.

CLRs have been exploited for their diverse therapeutic potential. Signals from CLRs initiate the development of adaptive immunity, especially Th1 and Th17 responses. DEC-205 and CLEC9A have the potential to be used as targets in cancer vaccine design, and synthesized ligands of Mincle have been developed to preferentially augment immunological responses. CLRs are vital in immunological synapse formation, DC trafficking, inducing humoral and cellular immunity, and linking both natural and adaptive immune responses (Apostolopoulos et al., 2013; Jang et al., 2015).

References
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van Kooyk, Y., & Rabinovich, G. A. (2008). Protein-glycan interactions in the control of innate and adaptive immune responses. Nature Immunology, 9(6), 593 601. Available from https://doi.org/10.1038/ni.f.203.

Dambuza, I. M., & Brown, G. D. (2015). C-type lectins in immunity: Recent developments. Current Opinion in Immunology, 32, 21 27. Available from https://doi.org/10.1016/j. coi.2014.12.002.

Chiffoleau, E. (2018). C-type lectin-like receptors as emerging orchestrators of sterile inflammation represent potential therapeutic targets. Frontiers in Immunology, 9. Available from https://doi.org/10.3389/fimmu.2018.00227.

Apostolopoulos, V., Thalhammer, T., Tzakos, A. G., & Stojanovska, L. (2013). Targeting anti gens to dendritic cell receptors for vaccine development. Journal of Drug Delivery, 1 22. Available from https://doi.org/10.1155/2013/869718.

Jang, J. H., Shin, H. W., Lee, J. M., Lee, H. W., Kim, E. C., & Park, S. H. (2015). An overview of pathogen recognition receptors for innate immunity in dental pulp. Mediators of Inflammation, 2015. Available from https://doi.org/10.1155/2015/794143.

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