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 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 1  |  Page : 13-22

C-type lectin receptors in skin immunity: Emerging new role for CLEC12B

1 INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d’Azur, Nice, France
2 INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d’Azur, Nice, France; Department of Dermatology, University Hospital of Nice, Université Côte d’Azur, Nice, France

Date of Submission13-Dec-2021
Date of Acceptance24-Dec-2021
Date of Web Publication19-Jan-2022

Correspondence Address:
Meri K Tulic
Team 12, C3M INSERM U1065, Batiment Archimed, 151 route Saint-Antoine de Ginestière, 06204 Nice Cedex 3.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/abhs.abhs_20_21

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C-type lectin receptors (CLRs) are a superfamily of transmembrane proteins, which consist of one or several C-type lectin-like domains and intracellular signaling motifs, such as immunoreceptor tyrosine-based activation motif (ITAM) or immunoreceptor tyrosine-based inhibitory motif (ITIM). CLRs are mostly expressed on antigen-presenting cells and are known to play an important role in both innate and adaptive immunity. As a result, CLRs are involved in numerous physiological functions due to their ability to recognize pathogen-, tumor-, and damaged-associated molecular patterns on pathogens and host cells acting as pattern recognition receptors (PRRs). These immune receptors can respond to signals from the surrounding environment which has a direct and profound effect on the skin, the largest organ in the body and the only one that is in direct contact with the external environmental stimuli. The skin is colonized by a plethora of microorganisms constituting the skin microbiota and plays a central role in host defense against potentially pathogenic microbes including bacteria, fungi, and viruses. Skin dysbiosis has been shown to play a critical role in initiation of skin disease and/or induction of a local inflammatory environment. In this review, we discuss what is known about CLRs in skin immunity and their contribution to skin disease, with a special focus on a newly identified and a promising new CLR, CLEC12B.

Keywords: CLEC12B, C-type lectins, melanoma, pigmentation, skin immunity

How to cite this article:
Blot L, Passeron T, Tulic MK. C-type lectin receptors in skin immunity: Emerging new role for CLEC12B. Adv Biomed Health Sci 2022;1:13-22

How to cite this URL:
Blot L, Passeron T, Tulic MK. C-type lectin receptors in skin immunity: Emerging new role for CLEC12B. Adv Biomed Health Sci [serial online] 2022 [cited 2022 Dec 7];1:13-22. Available from: http://www.abhsjournal.net/text.asp?2022/1/1/13/335722

  Background Top

Lectins were first defined as carbohydrate-binding proteins or glycoproteins agglutinating cells and/or precipitating glycoconjugates. They are found in many organisms and may be soluble or membrane-bound [1]. Lectins can be classified in several categories, but here we are focusing on the C-type lectin receptors (CLRs), originally thought to bind ligands only in the presence of Ca2+ through conserved residues within their carbohydrate recognition domain (CRD). However, many CLRs have an extracellular domain similar to the CRD lacking the components necessary for Ca2+-dependent carbohydrate recognition [2]. Such domains are called C-type lectin-like domains (CTLDs) and they can bind a wide variety of ligands],[ other than carbohydrates],[ such as proteins],[ lipids],[ and inorganic compounds [3].

CLRs are a superfamily of more than 1000 proteins divided into 17 groups based on functional and structural characteristics. Usually classified as activating or inhibitory receptors based on their intracellular signaling motifs],[ some CLRs can induce both positive and negative signals depending on the binding ligand or the environment in order to shape diverse biological responses [4]. They are involved in numerous physiological functions due to their ability to recognize pathogen-, tumor-, and damaged-associated molecular patterns on pathogens and host cells. Most CLRs are expressed on antigen-presenting cells and were shown to play an important role in both innate and adaptive immunity [5]. Upon ligation],[ CLRs can act as innate immune pattern recognition receptors (PRRs) and internalize antigens for presentation to T cells],[ but also trigger cytokine production and expression of co-stimulatory molecules. Thus],[ CLRs play also a key role to instruct adaptive immunity through T-cell polarization],[ attraction of other immune cells],[ antibody production as well as immunological memory formation [6],[7].

CLRs can respond to external signals from the environment and the skin],[ representing the largest organ in the body],[ is the most exposed interface with all the environmental stimuli. The skin is colonized by a plethora of microorganisms],[ representing the skin microbiota],[ and plays a central role in host defense against potentially pathogenic microbes including bacteria],[ fungi],[ and viruses [8]. To sense these pathogens],[ different types of skin cells express a broad range of PRRs],[ including CLRs],[ so that they can recognize and discriminate pathogens from commensal microorganisms to maintain skin homeostasis. Dysregulation of this microbiota can initiate diseases and/or an inflammatory environment.

Rather than providing a complete description of all the CLRs involved in immune homeostasis and skin diseases],[ already well described by other recent reviews],[ [7],[9] here we focused on what is known about CLRs in skin immunity with a special focus on a newly identified and an emerging role of still poorly understood CLR, CLEC12B.


Antitumor activity is essential for detection and killing of tumor cells. Both innate cells, such as natural killer (NK) cells, and acquired immune cells, especially cytotoxic CD8+ T cells, play important roles in the eradication of tumors. However, some cells can interfere with the antitumor immunity, like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Cancer cells can also inhibit the antitumor activity through the interaction between PD-L1 and/or PD-L2, expressed by tumor cells, and PD-1 at the surface of cytotoxic T cells [9]. CLRs are key players of the immune surveillance system and are thought to recognize tumor-specific antigens or neo-antigens to activate anti-tumor immunity],[ but their precise implication in these immune processes is not fully understood yet.

Melanoma is a very deadly skin cancer arising from melanocytes transformation. Recent reports have highlighted the important role of Dectin-1 (CLEC7A) in melanoma suppression [10-12]. Dectin-1],[ for Dendritic Cell-Associated C-type Lectin 1],[ is a type II membrane receptor with a single CTLD and a hem-immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. It is part of the Dectin-1 cluster with six other CLRs],[ all encoded in the same locus in both mouse and human genomes [13]. Dectin-1 expressed by dendritic cells (DCs) and macrophages recognize N-glycan structures on melanoma cells and induce the activation of the IRF5-INAM pathway [10],[14]. The interferon regulatory factor 5 (IRF5) is a transcription factor involved in the induction of class I interferons and inflammatory cytokines and its activity is critical to induce expression of IFN regulatory factor 3-dependent NK-activating molecule (INAM). This leads to the activation of NK cells through a cell-to-cell contact with DCs which is necessary to enhance the NK cell-mediated killing against melanoma cells [10]. Interestingly],[ Dectin-1 expressed on NK cells has minor effects on the tumor-killing activity. Another study has shown an antitumor immunity in melanoma through the activation of DCs by curdlan],[ a selective Dectin-1 agonist. Dectin-1 signaling induces Th9 cell differentiation and production of interleukin-9 (IL-9)],[ leading to an antitumor immunity [11]. More precisely],[ Dectin-1-activated DCs present an enhanced IL-33 expression],[ leading to a Th9 priming and antitumor immunity. Blocking IL-33 inhibits the Th9 priming by Dectin-1-activated DCs while adding IL-33 to Dectin-1-activated DCs increases the CD4+ proliferation and inhibits the IL-33-induced Treg priming [12]. Altogether],[ these results could bring new means for an effective tumoricidal action using Dectin-1 agonistic antibodies or perhaps a combination of Dectin-1 and IL-33 may present a new effective modality of DC-based vaccines in melanoma immunotherapy. Recently],[ C-type lectin domain family 12 m ember B (CLEC12B) has been shown to play a role in melanoma],[ but we’ll present these results later in this review.

CRLs can also serve in antitumor vaccination. For example],[ DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN],[ CLEC4L)],[ a type II membrane receptor with one CTLD expressed as a tetramer on DCs],[ recognizes a wide range of pathogens and can present antigens to MHC-I and MHC-II molecules after internalization in antigen-presenting cells (APCs). This leads to increased CD4+ and CD8+ T cell responses. In a recent study],[ generation of apoptotic tumor cell-derived extracellular vesicles (ApoEVs) presenting melanoma antigens induced the expression of high-mannose glycans. The DC-SIGN binding to such high-mannose glycans increases the antigen internalization efficiency],[ resulting in enhanced priming of melanoma-specific CD8+ T cells [14]. These results highlight the importance of using CLRs as promising vaccination tools Ito shape antitumor T cell responses.


Fungi are omnipresent in our environment and the host-associated fungal populations represent the mycobiota. Although only a few fungal species are considered pathogenic and induce fungal infections],[ recent studies highlight a pivotal role for the mycobiota in modulating homeostasis and disease susceptibility [15]. Human fungal skin infections are usually superficial],[ but some fungal species can also lead to extensive skin and subcutaneous tissue infections. Fungal ligands activate a variety of PRRs including CLRs to induce an innate immune response through direct killing of fungi],[ modulation of mycobiota],[ and priming of adaptive immune responses. These CLRs can be expressed by skin myeloid cells divided into Langerhans cells (LCs) residing in the epidermis or DCs residing in the dermis. Understanding the role of CLRs in shaping host-fungi interaction and fungal disease susceptibility is necessary to find new therapeutic strategies against fungal diseases [16].

Candida albicans is one of the predominant fungi species present in the human mycobiota and usually asymptomatically colonizes many niches in healthy individuals],[ including the skin. However],[ a fungal dysbiosis can promote the pathogenicity of C. albicans leading to infections from superficial dermal infections to systemic ones [17]. During C. albicans skin infection],[ yeast forms are found in the epidermis and invasive filamentous forms in the dermis. On one hand],[ the yeast form is recognized by Dectin-1 on LCs in the epidermis],[ leading to an increased production of IL-6 and thus to a Th17 cell differentiation. On the other hand],[ the filamentous form is recognized by dermal DCs],[ thus leading to a Th1 cell differentiation [18]. Interestingly, the addition of Dectin-1 ligands, such as curdlan, rescues the ability of filamentous forms to generate Th17 cell response. This suggests that there is no Dectin-1 ligature in the dermis during a C. albicans infection but dermal DCs do have the ability to prime Th17 cells. The morphologic change of C. albicans from the epidermis to the dermis could be an adaption to evade immune responses driven, among others, by Dectin-1. In this in vivo study, Th17 cells provide protection against skin challenges whereas Th1 cells provide systemic protection [18]. These results reveal a key role of Dectin-1 binding in driving T helper cells responses that provide tissue-specific protection in response to C. albicans morphology. However, another study shows that the C. albicans filamentous form can induce Th17 responses through the production of IL-1β by macrophages [19]. These in vitro methods, using cocultures of macrophages with lymphocytes to measure IL-17 production, describe a Dectin-1/inflammasome pathway as a mechanism that provides a protective Th17 response against C. albicans infection. These conflicting data could be explained by the different cellular types used in these two studies (e.g., LCs and DCs versus macrophages) and more importantly, the physiological differences between in vivo and in vitro studies. Notably, the different Dectin-1 binding between LCs in the epidermis and dermal DCs leading to different T cell responses cannot be found in cocultures where exogenous Dectin-1 ligands are added to macrophages and lymphocytes.

Dectin-2, for Dendritic Cell-Associated C-type Lectin 2 (CLEC6A), is also a major fungal PRR that can signal via Syk pathway to activate DCs and regulate adaptive immune responses to fungal infections. Unlike Dectin-1, Dectin-2 requires an association with FcRγ chain for surface expression and coupling to Syk. Although Dectin-2 isn’t necessary for innate resistance to C. albicans infection, it has an essential role in Candida-specific T cell production of IL-17 [20].

Many studies describe how the collaboration of different CLRs can shape specific immune responses to pathogens. Fonsecaea monophora is a causative agent of chromoblastomycosis which is a chronic fungal skin infection. This fungal pathogen activates Dectin-1 leading to the activation of the interferon regulatory factor 1 (IRF1) and an enhanced IL-12A transcription for an antifungal Th1 polarization. However],[ F. monophora also binds Mincle (Macrophage-inducible C-type lectin],[ CLEC4E)],[ a CLR within the Dectin-2 cluster interacting with the FcRγ chain which activates protein kinase B (PKB) and induces the proteasomal degradation of IRF1 via an E3 ubiquitin ligase Mdm2],[ leading to an inhibition of IL-12A transcription. Thus],[ the decreased production of IL-12p35 by human DCs induces a Th2 polarization instead of a Th1 differentiation. This study reveals how the engagement of a CLR],[ Mincle],[ can suppress the antifungal immunity mediated by another CLR],[ Dectin-1],[ thus making Mincle a potential therapeutic target to redirect Dectin1-induced Th responses [21].

Beyond its protective role against UV damage in human skin],[ melanin (and more specifically eumelanin) has also antioxidant properties and a protective role against free radicals [22]. However, melanin can be considered as a fungal virulence factor, protecting fungi from the host immune defense by inhibiting host-cell phagocytosis, cytokine production, and apoptosis. MelLec (melanin sensing C-type lectin receptor, CLEC1A), another CLR of the Dectin-1 cluster with one CTLD and an immunoreceptor tyrosine-based inhibitory motif (ITIM) which is expressed by endothelial cells and myeloid cells, can recognize melanized fungal species, more specifically DHN-melanin produced from A. fumigatus conidia and other DHN-melanized fungal species [23]. The sensing of fungal DHN-melanin by MelLec is crucial in the control of systemic A. fumigatus infection. It has been shown that an single nucleotide polymorphism in the coding region of MelLec],[ more precisely an amino acid change Gly26Ala in the cytoplasmic tail],[ increases the risk of disseminated aspergillosis in stem-cell transplant recipients when the variant is carried by the cell donor. Thus],[ MelLec might have a myeloid cell-mediated protective role and the identification of donors carrying this single nucleotide polymorphism could help to reduce the incidence of aspergillosis in transplant recipients. These results highlight the importance of melanin in effective fungal pathogenesis as well as in immune defenses against fungal infections],[ making the fungal melanin system a pertinent target for drug discovery [24].


As mentioned],[ the skin is constantly exposed to potentially pathogenic microorganisms],[ including viruses. Recognition of viruses by CLRs is complex and crucial as they can recognize and quickly respond to viral PAMPs to shape immune responses and inhibit viral spread within the host. However],[ some viruses are opportunistic as they can use the CLR machinery to enter host cells],[ to impair signaling pathways],[ and to inhibit APC functions [25]. Thus],[ viruses can avoid immune recognition and antiviral immunity to freely infect host cells.

Human immunodeficiency virus-1 (HIV-1) is mainly sexually transmitted across genital mucosa and establishes a life-long infection when viral DNA succeeds to integrate host genome. It has been shown that DC-SIGN is highly expressed on DCs in mucosal tissues and can bind to HIV-1 glycoprotein gp120 at the surface of immature DCs. Instead of internalizing gp120 into DCs for presentation to T cells and subsequent antiviral immunity],[ DC-SIGN is exploited by HIV-1 in that it doesn’t allow virus entry but captures it to facilitate infection in trans of CD4+ T cells in the lymph nodes through binding of gp120 to CD4 [26]. Another study showed that HIV-1 also binds to monocyte-derived macrophages],[ which lack DC-SIGN on their surface],[ through the macrophage mannose receptor (MMR)],[ a CLR from the mannose receptor family that can recognize high-mannose oligosaccharides on foreign particles. In a similar way to DC-SIGN],[ MMR binds to gp120 and captures HIV-1 to mediate transmission of bound virus to T cells. However],[ HIV-1 longevity is decreased when bound to macrophages in comparison to DCs because of endocytosis-mediated internalization of the virus [27]. These are examples of how a virus can escape antigen processing by hijacking CLRs. Fortunately, some CLRs do protect us against viruses such as HIV-1. In fact, DC-SIGN and MMR can be found on dermal DCs but Langerin (Langerhans cell-specific C-type lectin, CLEC4K) is a type II membrane receptor for mannose expressed on epidermal LCs, [28] meaning that Langerin is the first CLR to encounter HIV-1 in the skin. Langerin binds efficiently to HIV-1 on immature LCs and inhibits LC infection by internalizing and degrading infectious viral particles within Birbeck granules, thus preventing any viral spread to T cells [29]. However],[ the protective function of Langerin can be sabotaged if the protective layer of LCs in the epidermis is breached],[ allowing the virus to access to the subepithelial layers of dermal DCs or if there is a maturation of LCs],[ thus decreasing Langerin expression],[ or in case of high viral titers. Altogether],[ their results highlight the crucial involvement of CLRs in HIV-1 pathogenesis.


The microbial and host factors of the different skin niches drive the microbiota composition. For example],[ Staphylococcus and Cutibacterium bacteria are mainly found in sebaceous areas whereas Corynebacterium],[ Staphylococcus],[ and beta-Proteobacteria are rather in moist areas. But this composition can be drastically changed and skin homeostasis disrupted during inflammation processes and diseases [8]. Most of bacterial species found on the skin are commensal or beneficial for our health but there are also pathogenic bacteria],[ such as Staphylococcus aureus and Streptococcus pyogenes],[ which can cause local skin or even systemic infections. Bacterial PAMPs can be recognized by different PRRs on skin resident APCs],[ including CLRs],[ so that they can discriminate the good guys from the bad guys in this plethora of microorganisms. But just like viruses],[ some bacteria can exploit CLR interactions to avoid immune recognition and escape antibacterial immunity.

Langerin can interact with both Gram-positive bacteria S. aureus and S. pyogenes[30],[31].Staphylococcus aureus expresses on its surface a wall teichoic acid (WTA) which is a determinant glycopolymer driving host-pathogen interactions. Langerin actually recognizes a particular epitope on this WTA],[ β-GlcNAc],[ which is present in almost all S. aureus strains],[ whereas Langerin ligand on S. pyogenes is still unknown [30]. This binding increases the expression of co-stimulatory molecules and the production of Th1- and Th17-proinflammatory cytokines, thus inducing skin inflammation. Although Langerin does not interact with α-GlcNAc, the co-expression of this WTA epitope decreases β-GlcNAc binding and impairs LC responses and pro-inflammatory cytokines production [31]. Moreover],[ another type II membrane CLR named MGL (Macrophage galactose-type C-type lectin],[ CLEC10A) interacts with this α-GlcNAc motif on a particular S. aureus lineage],[ thus increasing pro-inflammatory cytokine production by monocyte-derived DCs [32]. These results suggest that S. aureus could evade immune surveillance through the modulation of its own WTA glycoprofiles and subsequent inflammatory responses. In addition],[ Langerin on epidermal LCs and DC-SIGN on dermal DCs can also interact with another bacterium that can be found on the skin],[  Yersinia More Details pestis],[ a Gram-negative pathogen causing the plague [33],[34]. Yersinia pestis More Details is phagocytosed and can invade LCs and DCs through the recognition of the core oligosaccharides of LPS on its surface by Langerin and DC-SIGN],[ respectively. After being captured by these APCs],[ Y. pestis is delivered to lymph nodes to establish infection and spread across the host body. This mechanism is similar to HIV-1 infection through hijacking of DC-SIGN in order to be captured and transmitted to lymph nodes to spread the infection],[ as mentioned earlier. However],[ the protective function of Langerin against HIV-1 does not apply here],[ as Y. pestis exploit these two CLRs to evade antibacterial immunity and to infect the host. Taken together],[ these studies highlight the importance of CLRs in antibacterial immunity and the need to find therapeutic targets that can block the CLR/pathogen interactions.


Psoriasis is a chronic inflammatory skin disease characterized by sharply defined],[ erythematous plaques with silvery scaling. It has been suggested that PAMPs from pathogens and commensal microbiota or alarmins from dead skin cells can activate some CLRs such as Dectin-1 at the surface of LCs [9]. It results in a production of pro-inflammatory cytokines by LCs but also by keratinocytes in the skin and the recruitment of γδ T cells and group 3 innate lymphoid cells (ILC3s) to the inflammatory sites. This leads to the recruitment of neutrophils and the activation of keratinocytes to produce inflammatory molecules and antimicrobial peptides],[ inducing inflammation and keratinocytes proliferation. These innate immune responses have a key role in development of psoriasis [9]. LCs from normal human skin do not express the type I membrane CLR MR (Mannose receptor],[ CLEC13D) whereas inflammatory epidermal DCs from patients with atopic dermatitis or psoriasis are positive for MR and use it for receptor-mediated endocytosis of mannans [35]. Another study shows that an injection of mannan into mice activates pathogenic inflammatory macrophage responses],[ leading to the development of psoriasis],[ psoriatic arthritis],[ and chronic rheumatoid-like arthritis. MR is one of the receptors binding to mannan and the loss of its expression],[ in addition to a ROS deficient environment],[ causes more severe diseases. Importantly],[ the protective effect of MR is associated with a ROS-dependent regulation of immunosuppressive M2 macrophages [36]. However],[ MR and DC-SIGN are expressed in CD163+ macrophages and these dermal macrophages are increased in psoriasis in comparison to normal skin and do not express mature DC markers. This subpopulation of activated macrophages produces key inflammatory molecules and contributes to the pathogenic inflammation in psoriasis [37]. In view of these results],[ the exact role of MR and other CLRs is still unclear in the development of psoriasis and further studies need to be done to elucidate the exact mechanisms.

The spondyloarthropathies],[ including psoriatic arthritis],[ cause chronic inflammation of the axial joints],[ and are thought to be triggered by an abnormal immune response to infection. Some genes associated with this group of diseases are part of the inflammatory Dectin-1/Syk pathway. Administration of curdlan in SKG mice],[ a model of chronic autoimmune arthritis],[ shows the development of psoriasiform dermatitis through Dectin-1 ligation and suggests the involvement of innate immunity in this mechanism [38].

Vitiligo is a chronic autoimmune disease characterized by skin and hair depigmentation due to melanocytes loss. Recently],[ our laboratory has shown that under stress],[ innate immune cells such as NK and ILC1s in vitiligo skin produce a large amount of IFNγ that induces the secretion of chemokines by keratinocytes and melanocytes [39]. These chemokines bind to their receptor CXCR3B at the surface of melanocytes inducing their initial apoptosis and release of self-antigens. The remaining melanocytes express co-stimulatory and adhesion molecules which present the self-antigens to the naive T cells attracted by the chemokines. Thus],[ the remaining melanocytes are destroyed by CD8+ T cells],[ leading to skin depigmentation [40]. Interestingly, Natural Killer Group 2D (NKG2D) is expressed in both NK and CD8+ T cells but has different mechanisms of action depending on the cell type. NKG2D is a C-type lectin-like receptor encoded by KLRK1 gene which is located within the NK complex among other CLRs such as Dectin-1 and MelLec. NKG2D is an activator of NK cell cytotoxicity with a broad range of ligands whereas it is a co-stimulatory molecule requiring TCR activation on CD8 T cells [40]. It has been shown that NKG2D which is expressed by CD8+ effector memory T cells],[ and its ligands are increased in perilesional skin of vitiligo],[ leading to the production of pro-inflammatory cytokines [41]. Along with other studies],[ these data suggest that the recognition of stressed/damaged cells by NKG2D could induce the CD8+ T cell-mediated melanocyte killing in vitiligo skin [42]. Despite the great progress that has been made throughout the past decades in elucidating the mechanisms that cause vitiligo],[ there is still no cure],[ but a number of promising therapeutic targets focusing on modulation of innate immunity are emerging [43].


The C-type lectin domain family 12 member B],[ also named CLEC12B],[ is part of the Dectin-1 cluster with six other CLRs including CLEC12A],[ CLEC1B],[ CLEC9A],[ CLEC1A],[ CLEC7A],[ and CLEC8A],[ classified within the group V of CLRs [44]. Although it represents the larger CLR family],[ it is of importance to highlight that the ligands],[ partners],[ and functions of CLEC12B are largely unknown and are only beginning to be understood [13]. This gene is found on mouse chromosome 6qF3 and on human chromosome 12p13.2 and is thought to be expressed in normal human tissues including testis, skin, spleen, and in the bone marrow [45]. Notably],[ the human and murine homologs of CLEC12B show typical features of C-type lectin-like receptors i.e.],[ amino acid sequences],[ exon-intron structure],[ and protein domains. According to a phylogenetic study],[ CLEC12B is most closely related to Dectin-1 within this gene cluster [46].


CLEC12B has been identified by Hoffman et al.[47] as an inhibitory receptor on myeloid cells, named after CLEC12A due to their high similarity in structure, function, and chromosomal location. In fact, CLEC12A has been first identified as a myeloid inhibitory CLR, whose gene is also located in the Dectin-1 cluster and is variably spliced, which can recruit both phosphatases SHP1 and SHP2 through its ITIM domain [48]. CLEC12B was thought to be a potential inhibitory counterpart of NKG2D],[ because of their high homology in the extracellular domain. However],[ there was no match in ligand specificity of both receptors and CLEC12B ligands are still to be found. Expression of full-length transcript was found in various tissues except for the brain],[ in addition to a spliced variant transcript lacking exon 4 and thought to code a non-functional protein. In fact],[ CLEC12B is found to be differentially spliced because of two independent alternative splicing events. The mRNA coding for a functional type II transmembrane protein shows a cytoplasmic tail containing an ITIM domain connected via a transmembrane domain and a stalk domain to a CTLD. However],[ the three other spliced variants are thought to code truncated and probably non-functional proteins [46] [Figure 1]. It appears that there exists a fifth CLEC12B transcript variant represented as non-coding because of a nonsense-mediated mRNA decay (NM_001387138.1). At the protein level, CLEC12B is expressed on the human promyelocytic cell line U937 only after phorbol 12-myristate 13-acetate (PMA) stimulation and on in vitro differentiated macrophages but not on freshly isolated monocytes or any other blood leukocyte population [47]. Another study identified the porcine homolog of CLEC12B which is expressed on alveolar macrophages],[ blood DCs and plasmacytoid DCs but not on monocytes],[ monocyte-derived macrophages],[ or monocyte-derived DCs [49]. To assess CLEC12B function],[ a mutant form has been generated by exchanging the tyrosine residue by a phenylalanine within the ITIM domain so that it can no longer be phosphorylated. Thus],[ it has been shown that upon phosphorylation of this ITIM],[ CLEC12B can recruit tyrosine phosphatases SHP1 and SHP2 and act as an inhibitory receptor to reduce the effect of kinases in ITAM-mediated pathways],[ in particular to inhibit NKG2D-mediated NK cell cytotoxicity [47]. Beyond its ligation to SHP1 and SHP2],[ CLEC12B is thought to be a putative interaction partner of caveolin-1],[ a structural protein involved in a variety of cellular functions [50].
Figure 1: CLEC12B isoforms. The transcript variant 1 shows a cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) connected via a transmembrane domain and a stalk domain, to a C-type lectin-like domain (CTLD). The transcript variant 2 differs in the 3′ coding region and 3′ UTR compared to variant 1. The resulting protein (isoform 2) has a shorter, distinct C-terminus compared to isoform 1. The transcript variant 3 uses an alternate splice site in the central region and initiates translation at a downstream start codon compared to variant 1. The resulting protein (isoform 3) has a shorter N-terminus than isoform 1. The transcript variant 4 uses an alternate splice site in the central region, initiates translation at a downstream start codon, and differs in the 3′ coding region and 3′ UTR compared to variant 1. The resulting protein (isoform 4) has a shorter N-terminus and a shorter, distinct C-terminus compared to isoform 1. The transcript variant 5 uses an alternate splice site in the 3′ region compared to variant 1. This variant is represented as non-coding because the use of the 5′-most expected translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD)

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Recently],[ our laboratory has identified CLEC12B as a melanocytic gene through a transcriptional analysis of the lesional and non-lesional skin of vitiligo patients in comparison to skin samples of healthy subjects. This analysis showed a strong decrease in key genes involved in melanogenesis in biopsies from lesional skin characterized by a total absence of melanocytes],[ and CLEC12B was listed among the top melanocytic genes along with dopachrome tautomerase (DCT)],[ melan-A (MLANA)],[ or tyrosinase (TYR) [51]. We also have shown that CLEC12B is significantly more expressed in melanocytes compared to fibroblasts and keratinocytes],[ which are the main cell types in the skin [52]. These results are in accordance with RNA sequencing dataset from The Human Protein  Atlas More Details highlighting that melanocytes are the main cell type expressing CLEC12B],[ even if it was first identified as a CLR on myeloid cells [47]. We have demonstrated that CLEC12B expression is determined by our skin color whereby the highest expression is seen in light-skin individuals and decreased in highly pigmented skin. Furthermore],[ we have shown that CLEC12B modulates pigmentation in vitro and in reconstructed human epidermis through direct recruitment and activation of SHP1 and SHP2 through its ITIM domain. More precisely],[ CLEC12B downregulates melanogenesis proteins through the degradation of the c-AMP response element-binding protein (CREB)],[ which is a major transcription factor of melanocyte-inducing transcription factor (MITF) expression [53] [Figure 2]. Taken together, these results demonstrate, for the first time, a regulatory and a physiological function of CLEC12B in the human skin. These insights open exciting new perspectives for potential treatment of pigmentary diseases.
Figure 2: CLEC12B signaling pathways and function in the skin (ligands still unknown). (A) In normal skin, CLEC12B recruits both SHP1 and SHP2 through its ITIM domain and decreases their phosphorylation. The with these two phosphatases leads to a downregulation of MITF and downstream melanocytic genes (TYR, DCT, TRP1) through CREB proteasomal degradation. Thus, CLEC12B inhibits melanogenesis and subsequent skin pigmentation [52]. (B) In melanoma skin, CLEC12B recruits SHP2 through its ITIM domain and decreases its phosphorylation. This interaction induces a dephosphorylation of STAT3, leading to the inhibition of cell cycle and proliferation in particularly through an increased expression of p21, p27, and p53. Thus, CLEC12B inhibits tumor growth and subsequent melanoma progression [64]

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CLEC12B seems to be involved in several diseases but its exact role and function in these pathological processes remain unknown. In the context of skin, CLEC12B expression is significantly increased in chronic otitis with choleastomas in comparison to healthy skin, and compared to expression of various other CLRs [54]. Furthermore],[ during the transition from acute to asymptomatic stage in HIV-1 infection],[ a lot of immunosuppressive genes including CLEC12B are increased in order to modulate the immune system and therefore slow down the disease progression [55]. In patients with a severe form of Behçet’s syndrome],[ CLEC12B is part of a set of inhibitors of inflammation that are downregulated in comparison to patients with milder syndrome and/or controls],[ suggesting a pro-inflammatory response characteristic of this syndrome],[ whereas the increased expression of these negative regulators in milder syndromes may protect against severe forms [56]. CLEC12B is differentially expressed in non-ST-segment elevation myocardial infarction (NSTEMI) [57] and is up-regulated in response to Renibacterium salmoninarum bacteria in Atlantic salmon during Bacterial Kidney Disease [58].

According to an exome sequencing of a family with two children affected by ganglioneuroma and neuroblastoma],[ the presence of a potential deleterious mutation in a highly conserved region of the extracellular CTLD has made CLEC12B a candidate cancer predisposition gene [59]. The phosphatases SHP1 and SHP2 (interestingly both recruited by CLEC12B) have been associated with not only skin disorders but many cancers],[ including melanomas [60],[61]. Mutations in the PTPN11 gene],[ coding for SHP2],[ is a cause of pigmentary disorders such as Noonan or  LEOPARD syndrome More Details [62] and mutations in the PTPN6 gene, which codes for SHP1, causes inflammatory skin disorders [63]. In the context of melanoma],[ we have recently shown that CLEC12B plays an important role as a tumor suppressor gene in this skin cancer [64]. Melanoma patients with high CLEC12B expression have a significantly higher median survival than those with low expression. Notably, CLEC12B expression is lower in melanoma and melanoma metastasis than in melanocytic and benign melanocytic lesions. Functionally, we have demonstrated that CLEC12B inhibits melanoma growth through the recruitment of SHP2 on its ITIM domain that further inactivates signal transducer and activator of transcription (STAT) family of proteins (STAT 1, 3, and 5) [Figure 2] and increases p21, p27, and p53, in vitro and in vivo. Our results have recently been confirmed in a separate study showing a similar suppressor function of CLEC12B in lung cancer cells in vitro[65]. Together, these novel results support further studies investigating CLEC12B as a promising new therapeutic target in the treatment of melanoma and lung cancers however its application to other cancers remains to be investigated.

  Conclusion Top

In this review, we have focused on CLRs functions in skin immunity and have shown the extensive roles that this superfamily of proteins is involved in both normal skin physiology and pathology. During the past few years, great progress has been made to increase our knowledge about the complexity of their functions in a range of physiological processes including development, skin homeostasis, and skin pigmentation. Discovery of a novel gene, CLEC12B, and its role in skin pigmentation and melanogenesis warrants further exploration. Its newly discovered function involving the recruitment of phosphatases SHP1 and SHP2 through its ITIM domain confirms the original observations stating that CLEC12B inhibits NK cell cytotoxicity through the interaction with these two proteins. As previously mentioned, these phosphatases are linked to a broad range of biological processes and their interaction with CLEC12B is of interest considering the promising results for CLEC12B described in this review. Knowing that CLRs play a crucial role in immunity, it would be of interest to decipher the exact signaling pathways in CLEC12B-induced regulation. Future research focusing on discovering CLEC12B ligands is essential to facilitate future studies examining the exact role of CLEC12B in not only skin immunity but in other organs which may open new doors in the treatment of a number of immune disorders.

  Study limitations Top

The review is based on the analysis of the available literature. The data may lack some evidence from the clinical perspectives.

Authors’ contributions

LB prepared the draft of the review and Figure concepts. TP provided feedback and intellectual input into the review. MKT conceived the research concept and formulated review outline with LB. All authors reviewed and approved final draft of the manuscript. All authors are responsible for the contents and integrity of this manuscript.

Data availability statement

The authors will be glad to provide raw data of this research, if requested.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

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