The role of IL-31/IL-31R interactions in dendritic cells for the activation of human T cells
Interleukin-31 (IL-31) is a recently discovered four-helix bundle cytokine closely related to the IL-6 cytokine family. IL-31 mRNA expression was shown in several tissues, including bone marrow, kidney, colon and trachea. Among lymphoid and myeloid cells subsets, IL-31 mRNA was mainly detected in CD4+ T cells, suggesting that CD4+ T cells are the major cells type producing high amounts of IL-31. IL-31 signals through IL-31R signalling complex, which is a heterodimere composed of the IL-31Ralpha (IL-31RA) and the Oncostatin M receptor beta chain (OSMRB). IL-31RA was originally identified as gp130 like receptor and shows 28% homology to gp130, the common signalling receptor subunit of the IL-6 cytokine family. IL-31/IL-31R interactions result in the activation of Jak1, Jak2, STAT3, Erk1/2, PI3-kinase and Akt as shown in different gliobastoma cell lines, lung epithelial cells and colorectal cancer derived epithelial cell lines. Screening of different cell types revealed that IL-31R is most abundantly expressed on glioblastoma cells but is also present in epithelial cells and keratinocytes. Moreover, upon stimulation with IFN-gamma IL-31R expression could be detected in monocytes and macrophages.
So far, most studies have analysed the biological functions of IL-31 in skin diseases such as atopic dermatitis or allergic contact dermatitis. IL-31 transgenic mice develop strong pruritis, which is characterised by hyperkeratosis, infiltration of inflammatory cells into the skin and an increase of mast cells. In an experimental animal model for atopic dermatitis, IL-31 expression was clearly correlated with scratching behaviour. High IL-31 mRNA expression was further observed in skin biopsies taken from patients suffering from atopic dermatitis, allergic contact dermatitis or psoriasis. It was also shown that IL-31 may be a useful marker for the diagnosis of allergic asthma. Patients suffering from allergic asthma showed significantly higher serum levels of IL-31 protein and higher IL-31 mRNA expression in PBMCs compared to healthy individuals. Therefore, IL-31 was suggested to play an important role in the development and maintenance of atopic dermatitis and allergic asthma.
However, recently published studies support a role of IL-31/IL-31R interactions in limiting the severity of T helper (Th)2 mediated inflammation in the lung and the gut. After intravenous injection of Schistosoma mansoni eggs, IL-31RA deficient mice developed a more severe pulmonary inflammation compared to wild type (WT) animals. Ovalbumin (OVA) – pulsed macrophages generated from IL-31RA deficient animals promoted enhanced proliferation of OVA-specific CD4+ T cells compared to OVA-pulsed macrophages from control animals. In addition, naïve CD4+ T cells purified from IL-31RA deficient animals showed enhanced proliferation and secretion of Th2 cytokines upon polyclonal stimulation. These findings suggest that IL-31R signalling functions as negative regulator of type 2 responses in the lung by directly acting on macrophages and T cells. The observed suppression was clearly specific for Th2 responses since deficiency of IL-31RA did not enhance or alter Th1 responses. Another study describes that, in the absence of IL-31RA the severity of Trichuris muris (gastrointestinal helminth)-induced Th2 mediated immune responses are significantly increased as shown by enhanced Th2 cytokine secretion, increased IgE levels and an accelerated worm expulsion in IL-31RA deficient mice. Taken together these data indicate that IL-31 may play an important role in limiting Th2 mediated inflammatory responses. On the other hand several studies indicate that IL-31 is linked to the pathogenesis of atopic dermatitis. So far, the dichotomy in the effects of IL-31 remains poorly understood.
We speculate that IL-31 may contribute to the inhibition of Th2 mediated inflammation by shifting the balance of Th cell responses. It is well established that different types of CD4+ Th cells can develop from naïve T cells under the influence of polarizing signals. In particular, the type of cytokine produced in the early phase of an immune response is critically involved in the differentiation of naïve CD4+ T cells towards a specific Th subset. Dendritic cells (DCs) are the most potent antigen presenting cells and determine the fate of T cell responses. The characteristics of Th cell polarizing factors and the way in which DCs bias the development of different Th cell subsets, depends on the way in which DCs are activated.
Hence, the major aim of this project is to study the influence of IL-31 on DCs activation and furthermore the modulatory capacities of this cytokine in terms of downstream T cell activation and T cell polarization. In addition, we will investigate molecular mechanisms underlying IL-31 expression in T cells and IL-31RA expression in DCs.
This project is funded by the Austrian „Fond zur Förderung der Wissenschaftlichen Forschung“, Grant P22202.