IL-31 regulates DC-mediated T cell responses in the course of AD

Atopic dermatitis (AD) is a common inflammatory skin disease, often associated with other systemic disorders such as food allergy, allergic rhinitis and asthma. While the acute phase of AD is clearly characterized by a Th2 phenotype, other CD4+ T cell subsets, including Th1 and Th17 are involved in the pathogenesis of chronic AD. Dendritic cells (DCs) are the most potent activators of T cell responses and appear to be involved in the switch of Th cell responses. Therefore, they are considered to be important players in the clinical manifestation of the disease. Interleukin-31 (IL-31) is a type-I cytokine that is mainly released by activated T cells, in particular Th2 cells. While a clear association of IL-31 and the severity of AD has been shown in a number of studies, the contribution of IL-31 to the progression of the disease is not well understood. We recently found that the IL-31- receptor complex is highly expressed on human DCs upon IFN- treatment. Moreover, we showed that human DCs release a number of pro-inflammatory mediators upon IL-31 stimulation, indicating that DCs are an important target of IL-31. Based on our previous findings we hypothesize that IL-31 is crucially involved in DC-mediated activation of distinct T cell subsets, in particular IL-17 producing CD4+ Th cells. Moreover, we assume that IL- 31-triggered DCs derived from AD patients differ from those of control donors in their ability to activate specific T cell responses. The principal aim of this project is to investigate the role of IL-31-exposed DCs in the context of AD. Besides a detailed analysis of the activation/maturation state of IL-31-treated DCs and its consequences for T cell activation, we will also compare IL-31 receptor expression and IL-31-induced signaling pathways in DCs derived from AD patients and healthy subjects. Taken together, this study will analyze the function of IL-31 and its receptor on DCs and will scrutinize IL-31-triggered DCs as key players in the activation of T cell-mediated inflammation in the course of AD.

Atopic dermatitis (AD) is a chronic, eczematous skin disease which affects a large number of people worldwide. The disease is characterized by itchy and inflamed skin, and the symptoms can be significantly worsened by exposure to harsh detergents and low humidity. Furthermore, AD may be aggravated by related hypersensitivity afflictions such as pollen allergy and hay fever. AD is usually treated with topical steroids and moisturizing creams to alleviate symptoms; however, recent studies aimed at finding the underlying cause of AD as well as potential new treatments have focused on a molecule known as IL-31 that is secreted by certain cells of the immune system. In humans, elevated IL-31 levels have been closely correlated with the severity of AD. In line with this, mice genetically engineered to produce an abnormally high level of IL-31 develop a skin disorder that looks very similar to AD in humans. Thus, the application of drugs capable of lowering the level of IL-31 may be an effective way to treat AD. Indeed, new drugs targeting IL-31 have been developed, some of which are currently in clinical trials (e.g. anti-IL-31 antibodies and anti-IL-31 receptor antibodies). However, the detailed function of IL-31 in AD is still not well understood, and its involvement in related allergic diseases (like pollen allergy) that might exacerbate AD remains to be worked out. IL-31 exerts its function by binding to receptor molecules on the surface of certain cell types, eliciting a signaling cascade within the target cell to alter its behavior. In the first part of the project, we uncovered important elements of the signaling cascades induced by IL-31, including the signaling capacities of all five IL-31 receptor variants, features of the IL-31 receptor complex that are necessary for receptor signaling, and regulatory (feedback) mechanisms that normally keep IL-31-signaling under control. In the second part of the project, we investigated the role of IL-31 and its receptor in AD and pollen allergy. We discovered that not only are IL-31 levels abnormally high in AD patients, they are also elevated in the blood of pollen-allergic patients. Moreover, we identified basophils (important effector cells in allergic responses) as novel IL-31 target cells. Our data clearly establish that IL-31 is tightly associated with pollen allergy and demonstrate the increasing importance of IL-31 as key molecule in allergic diseases. Taken together, our discoveries have contributed to a better understanding of IL-31 and its mechanism of action. Our findings will help to improve the quality, and minimize any side effects, of new anti-allergy medications targeting IL-31 or the IL-31 receptor.