Dectin-2 Promotes House Dust Mite–Induced T Helper Type 2 and Type 17 Cell Differentiation and Allergic Airway Inflammation in Mice

Abstract

The fact that sensitization against fungi is closely related to the severity of asthma suggests that immune systems recognizing fungi are involved in the pathogenesis of severe asthma. Recently, Dectin-2 (gene symbol, Clec4n), a C-type lectin receptor, has been shown to function as not only a major pattern-recognition receptor for fungi, but also a receptor for some components of house dust mite (HDM) extract, a major allergen for asthma. However, the roles of Dectin-2 in the induction of HDM-induced allergic airway inflammation remain largely unknown. Our objective was to determine the roles of Dectin-2 in HDM-induced allergic airway inflammation. We examined the roles of Dectin-2 in the induction of HDM-induced T helper (Th) 2 and Th17 cell differentiation and subsequent allergic airway inflammation by using Clec4n-deficient (Clec4n(-/-)) mice. We also investigated Dectin-2-expressing cells in the lung and their roles in HDM-induced allergic airway inflammation. Clec4n(-/-) mice showed significantly attenuated HDM-induced allergic airway inflammation and decreased Th2 and Th17 cell differentiation. Dectin-2 mRNA, together with Dectin-3 and Fc receptor-γ mRNAs, was expressed in CD11b(+) dendritic cells (DCs), but not in CD4(+) T cells or epithelial cells in the lung. CD11b(+) DCs isolated from Clec4n(-/-) mice expressed lower amounts of proinflammatory cytokines and costimulatory molecules, which could lead to Th2 and Th17 cell differentiation than those from wild-type mice. HDM-pulsed Clec4n(-/-) DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed wild-type DCs. In conclusion, Dectin-2 expressed on CD11b(+) DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.

Monocyte differentiation and antigen-presenting functions

“…Although the first mechanism of monocyteinduced T cell suppression described above has been demonstrated multiple times, the other two mechanisms require further confirmation and investigation. In conclusion, various studies suggest that the functional role of LY6C + monocytes is largely dictated by the pathogen or inflammatory environment they encounter 79,[124][125][126] .…”

CD36 and Platelet-Activating Factor Receptor Promote House Dust Mite Allergy Development

“…Many studies have demonstrated that these and other innate receptors are involved in HDM allergy development; however, very few studies have clearly demonstrated to what extent engagement of these receptors on epithelial and/or dendritic cells contributes to allergic disease. These few studies detail how Dectin-2 on dendritic, but not epithelial, cells (18) and TLR-4 on epithelial, but not dendritic, cells (19) are involved in HDM allergy development.…”

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

“…Dectin-2 is also involved in the generation of both Th1 and Th17 responses to Candida glabrata (Ifrim et al, 2014) and it contributes to C. albicans-induced Th1 responses in collaboration with Dectin-1 (Robinson et al, 2009;Saijo et al, 2010). In addition to its role in antifungal responses, Dectin-2 also induces allergic inflammation in response to house dust mites through the production of cysteinyl leukotrienes and subsequent development of Th2 and Th17 responses (Barrett et al, 2011;Clarke et al, 2014;Norimoto et al, 2014;Parsons et al, 2014). Interestingly, Dectin-2 is also involved in regulating an autocrine IL-17 loop that controls the activation of a subset of neutrophils (Taylor et al, 2014).…”