Allergic diseases are mainly type 2 immune-mediated disorders characterized by the formation of specific IgE antibodies against innocuous substances called allergens. Allergic sensitization occurs after the first contact with the allergen, which is captured by DCs in the airways, gut, or skin. DCs process and transport the allergen to the drain lymph nodes where it is presented to naïve CD4+ T cells, leading to the generation of allergen-specific CD4+ Th2 cells. After IgE class-switching, B cells produce high amounts of allergen-specific IgE that bind to the high-affinity FcɛRI on mast cells and basophils, thus leading to patient’s sensitization [2, 25]. New allergen encounters trigger cross-linking of the IgE-FcɛRI complexes on mast cells and basophils, inducing the release of the anaphylactogenic mediators that are responsible for the immediate clinical symptoms. Memory allergen-specific Th2 cells activated via IgE-facilitated allergen presentation by DCs and B cells and type 2 innate lymphoid cells (ILC2) activated by epithelial cell–derived alarmins (TSLP, IL-33, and IL-25) produce large amounts of IL-4, IL-5, IL-9, and IL-13 contributing to maintain allergen-specific IgE levels, eosinophilia, mucus production, recruitment of inflammatory cell, and tissue inflammation, which are involved in the chronicity and the most severe clinical manifestations of allergy [2, 25].

The initiation of type 2 immune response prompted by allergens entails its uptake and processing by antigen-presenting cells, mainly DCs, a process that might be enhanced by specific CLRs. Common allergens such as Der p 1, Der p 2, Fel d 1, Ara h 1, Bla g 2, or Can f 1 are glycoproteins, many of which contain structurally related oligosaccharides. Compelling experimental evidence show that the common oligosaccharide structure on allergens is a pentasaccharide core, Man3-GlcNAc2, which often contains additional monosaccharides [11, 26]. CLRs, including dectin-1, dectin-2, DCIR, MR, and DC-SIGN, express on DCs and other myeloid immune cells can recognize carbohydrate structures on allergens, enhancing their uptake and also triggering different downstream signaling responses that might well promote type 2–mediated responses or tolerance depending on the specific CLRs engaged, the subsequent signaling pathways initiated, and the physical nature of the carbohydrate ligands as well as on the affinity and avidity of the carbohydrate-CLR interaction [7, 27]. In the next paragraphs, we will summarize the most recent findings related to the role of specific CLRs that have been involved in the recognition of different allergens and how this might regulate the initiation and maintenance of type 2 immune responses in the context of allergic diseases.

There are conflicting data about the role of dectin-1 in allergy. Murine models of HDM- and ovalbumin-induced airway inflammation have demonstrated that dectin-1-deficient (Clec7a−/−) mice displayed less eosinophilic and neutrophilic inflammation as well as Th2 and Th17 cells compared with wild-type mice [28, 29]. Dectin-1 expressed by CD11b+ DCs senses some glycans in the HDM extract and promotes allergic airway inflammation [28] (Fig. 2). Similarly, dectin-1 signaling has been proven to be essential for the development of Japanese cedar pollen–induced allergic rhinitis in mice [30] and participates in lung inflammation in a murine model of fungal allergy through the induction of IL-22 [31]. By contrast, it has been demonstrated that invertebrate tropomyosin (for example, Der p 10 in HDM) binds to dectin-1 at the mucosal surfaces and mediates protection against allergic diseases [32]. In addition, it has been demonstrated that dectin-1 is downregulated in the epithelium of allergic patients due to the aberrant production of IL-33 [33]. In line with these results, Gu et al. have described that dectin-1 activation suppressed allergic type 2 responses [34]. Although many research efforts have been made in understanding the role of dectin-1 in the promotion or prevention of type 2 immune responses to allergens, further studies are still needed to fully elucidate its actual role in allergic diseases.

CLR signaling in DCs drives Th2 responses. Allergens such as Der p 1 and Der p 2 from HDM (house dust mite), Can f 1 from dogs, Ara h 1 from peanuts, Bla g 2 from cockroaches, and Fel d 1 from cats are recognized and captured by C-type lectin receptors (CLRs) on dendritic cells (DCs) through their carbohydrates motifs and promote the polarization towards Th2 cells. DC-SIGN, DC-specific intercellular adhesion molecule 3-grabbing nonintegrin; TCR, T cell receptor; MHC-II, major histocompatibility complex class II

Dectin-2 is also involved in HDM-induced allergic airway inflammation as shown in different mouse models [35,36,37]. Notably, dectin-2-deficient mice display decreased eosinophilic and neutrophilic inflammation and Th2 responses in lung after HDM-induced sensitization [35]. Blocking of dectin-2 with specific antibodies inhibits HDM- as well as Der p 2-induced IL-5 and IL-13 production in cocultures of DC-T cells from asthmatic patients [38], which are characterized by an increased dectin-2 expression profile in peripheral blood mononuclear cells (Fig. 2) [39••].

Although DCIR is an inhibitory CLR, it has been involved in allergen processing and signaling. DCIR binds cockroach allergen Bla g 2 and mediates its uptake by human basophils and mast cells, leading to their activation and contributing to Th2 responses [40, 41]. In a mice model of atopic dermatitis, DCIR (DCIR−/−)–deficient mice exposed to Bla g 2 display an attenuation of allergen-induced skin inflammation compared to wild-type mice [41], suggesting that DCIR might well play a key role during skin sensitization and allergen-mediated inflammation in the context of atopic dermatitis.

MR has been involved in the recognition and internalization of different allergens from HDM (Der p 1 and Der p 2), dogs (Can f 1), cats (Fel d 1), cockroaches (Bla g 2), and peanuts (Ara h 1, Ara h 3) through their carbohydrate moieties [42,43,44,45]. MR-deficient DCs show a reduced capacity to capture these allergens, although other receptors could be also implicated (Fig. 2). Binding assays reveal that CTLD4-7 domains of MR mediate the binding of Der p 1, Der p 2, Can f 1, Ara h 1, and Bla g 2 [42]. However, Fel d 1 is a ligand of the MR cysteine-rich domain [45]. MR participates in the Th2 polarization imprinted by Der p 1 in DCs [42]. Similarly, a mice model of allergic rhinitis has showed that MR has an essential role in Th2 polarization induced by the airborne allergen Fel d 1 [45]. Interestingly, DCs from allergic patients express higher levels of MR and uptake Der p 1 more efficiently than DCs from healthy donors [43, 46]. On the other hand, MR-deficient lung macrophages have displayed reduced cockroach allergen uptake, and MR-deficient mice have showed increased lung inflammation and exacerbated Th2 responses, suggesting that MR might well also play a very important role in the attenuation of type 2 inflammatory responses to allergens in the airways [47]. Therefore, deeper investigations are still required to firmly elucidate the actual role of MR in the regulation of type 2 immune responses to allergens or tolerance induction within the context of different allergic diseases.

DC-SIGN has been also implicated in the immunopathology of allergy due to its capacity to recognize allergens from HDM (Der p 1), foods (Ara h 1), animal dander (Can f 1, Fel d 1), and pollens (BG-60) [48, 49]. The major peanut allergen Ara h 1 binds to DC-SIGN activating DCs and inducing the polarization towards Th2 cells [50]. It has been described that peanut agglutinin is also a ligand of DC-SIGN that activates DCs in vitro [51]. Other common allergenic foods such as soybean, tree nuts, chicken egg, and milk contain DC-SIGN-binding proteins, which have showed serum IgE-reactivity [51]. Allergens from HDM and chicken egg, Der p 2 and Gal d 2, are captured by human DCs through DC-SIGN binding and promote the priming of Th2 and Th22 responses [49]. The use of a DC-SIGN blocking antibody impairs Der p 2 and Gal d 2 uptake by DCs as well as Th2 and Th22 polarization [49]. It has also been reported that HDM allergen Der p 7 can activate DCs via DC-SING binding and lead to polarization of Th2 in vitro (Fig. 2) [52]. Native or heat-inactivated allergens from HDM extract are endocytosed through DC-SIGN, reducing DC-SIGN expression on the surface of DCs, but inducing signaling events that promote the generation of Th2 cells [53]. However, it has been also shown that DC-SIGN deletion in DCs promoted Th2 polarization in autologous cocultures of Der p 1–stimulated DCs with T cells, suggesting that the axis Der p 1-DC-SIGN might well also promote allergen-specific Th1 or regulatory responses able to impair type 2 polarization [54]. Under this scenario, it was previously described that Der p 1 due to its cysteine protease activity can cleave DC-SIGN but not MR, which might play also an important role in the amplification of type 2 immune responses, thus enhancing its allergenicity [55, 56]. Therefore, further studies are also needed to clarify the actual role of DC-SIGN in the context of allergic diseases within the different potential scenarios.