Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses

Abstract

Allergic diseases are often triggered by environmental allergens that induce dominant type 2 immune responses, characterized by the infiltrated T-helper type 2 (TH2) lymphocytes, eosinophils, and elevated TH2 cytokines. In addition to TH2 type immune responses, epithelial stress and injury linked to tissue remodelling are often observed, suggesting that epithelial cells may play important role in regulating allergic responses. Dendritic cells (DCs), the professional antigen-presenting cells with the capabilities of sampling allergens, are considered as the key player on instructing TH2 immune responses. Whether inflamed epithelium can regulate innate immunity, such as macrophages and DCs, which in turn instructs adaptive immunity has long been hypothesized. Studies of thymic stromal lymphopoietin (TSLP), an epithelial cells-derived cytokine, that can strongly activate DCs, provide important evidences that the epithelial barrier can trigger allergic diseases by regulating immune responses. The finding that OX40/OX40Ligand (OX40L) interactions are the molecular trigger responsible for the induction and maintenance of TH2 responses by TSLP-activated DCs provides a plausible molecular explanation for TSLP-mediated allergy. Recent progresses in characterizing the pro-inflammatory IL-17 cytokine family have added an additional layer of complexity on the regulation of allergic inflammation. TSLP-DCs can induce a robust expansion of TH2 memory cells and strengthen functional attributes by up-regulating their surface expression of IL-17RB (IL-25R), the receptor for cytokine IL-17E (IL-25), a distinct member of IL-17 cytokine family. IL-17E (also known as IL-25) produced by epithelial cells, and other innate cells, such as eosinphils, basophils, and mast cells, are shown to regulate adaptive immunity by enhancing TH2 cytokine productions. These exciting findings expand our knowledge of the complex immunological cascades that result in allergic inflammation and may provide novel therapeutic approaches for the treatment of allergic diseases.

Figure 1. TSLP and TSLPR structure and function

TSLP was discovered by its biological activity to promote B and T cell development. In the periphery, TSLP strongly activates myeloid dendritic cells that upregulate their surface TSLPR expression rapidly. The TSLPR is a heterodimeric complex composed of TSLPR and IL-7Rα chains. In T cell lines, TSLP stimulation induced strong activation and phosphorylation of STAT5, whereas unidentified molecules or pathways may exist downstream of TSLPR signaling in DCs.

Figure 2. TSLP initiate innate and adaptive allergic responses

Invaded pathogens or allergens can trigger mucosal epithelial cells or skin cells (keratinocytes, fibroblasts, and mast cells) to produce TSLP. TSLP can initiate innate allergic responses by activating immature DCs to produce chemokines IL-8, eotaxin-2, and Th2 attarcting chemokine TARC. TSLP can also costimulate mast cells to produce IL5, IL13, GM-CSF, and IL-6. TSLP-activated mDCs can migate into the draining lymph nodes to initiate adaptive allergic responses. TSLP-activated DCs express OX40L, which triggers the differentiation of naïve CD4+ T cells into inflammatory Th2 cells and the expansion of allergen-specific T_H2 memory cells.

Figure 3. OX40L and IL-25 (IL-17E) maintain chronic allergic responses

DCs activated by TSLP can expand and activate resident Th2 memory cells that upregulates the expression of proallergic molecules, including IL-25R, cystatin A, Charcot-Leydon crystal protein, and prostaglandin D2 synthase. During chronic allergic inflammation, infiltrated mast cells, eosinophils, basophils, and injured structural cells can produce IL-25 that can further enhance T_H2 cytokines production, in particular IL-5 and IL-13 by DC-activated T_H2 memory cells.