Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

Influence of TLR4 stimulated by LPS and factors in the micromilieu of DCs on naive T-cell priming by TLR-bearing DCs. Stimulation of TLR4 on DCs by LPS in an inflammatory microenvironment (A) induces the release of IL-12p70 by DCs, which promotes T-cell immune responses of the T_H1 type, whereas stimulation of TLR4 on DCs in the presence of histamine or TSLP (B) reduces the capacity of DCs to release IL-12p70 and favors immune responses of the Th2 type. TLR4 ligation together with IL-6 and TGF-β in the microenvironment (C) enforces DCs to produce IL-23, which channels the induction of T_H17 cells, whereas activation of DCs through TLR4 in the presence of tolerogenic soluble factors, such as TGF-β, IL-10, vitamin D3 (Vit-D), glucocorticoids (GCs), or vasoactive intestinal peptide (VIP; D) enhances their release of IL-10, TGF-β, and activation of indoleamine 2,3-dioxygenase (IDO), strengthening their tolerogenic properties and the outcome of T cells with regulatory functions (Treg).

Expression of TLRs by human and murine DC subsets. Blood/spleen DCs, DCs isolated from peripheral blood or spleen; sLCs, LCs from skin. Green, Positive; red, negative; white, no data available; yellow, not clear.

Proposed model for dysfunctions of TLR2 signaling on the levels of monocytes, macrophages, and mDCs and TLR9 signaling on pDCs in patients with AD, which might increase the susceptibility of patients with AD to microbial infections. HSV, herpes simplex virus; IDEC, inflammatory dendritic epidermal cell; Mac, macrophage; Mo, monocyte; SEB, Staphylococcus aureus enterotoxin B.

Ligation of CD14/TLR4 on oLCs by natural ligands, such as bacterial components in the micromilieu or adjuvants applied during vaccines combined with allergens binding to IgE molecules on the surface of oLCs, leads to the release of tolerogenic mediators, such as IL-10 by oLCs, and enforces their tolerogenic properties, partially also through upregulated expression of coinhibitory molecules, such as B7-H1. Therefore oLCs prime naive T cells primarily into regulatory T-cell subtypes with high forkhead box protein 3 (Foxp3) expression and IL-10/TGF-β release. Furthermore, oLCs promote the outcome of T_H1 cells in part through the production of IL-12 and IL-18. These TLR-mediated properties of oLCs might be useful in the context of sublingual allergen-specific immunotherapy.