Signal transduction and gene expression in the immune system

Immune cells protect the organism from invading pathogens and tumour cells. For this purpose, immune cells need to express specific genes, which are controlled by complex signalling mechanisms. These processes are investigated in our group.

Upon contact with antigens, the immune system has to distinguish between ‘self’ and ‘non-self’ in order to induce defence mechanisms against harmful antigens, while harmless antigens like food, plant pollen or the body’s own tissues should be tolerated. In some cases, failures of the host defence lead to severe immune disorders like immune-deficiencies or autoimmunity. Allergy is another case where this decision-making process has gone wrong. The correct decision of the immune system upon contact with plant pollen, house dust or cat hair is to tolerate them, because these agents by themselves are harmless. However, in diseases like hay fever, food allergy, or allergic asthma, the immune system defends the body against a perceived threat with mechanisms that normally act against worms and other parasites. Novel insights in regulatory events mediating allergic diseases may lead to improved prevention and new therapeutic strategies.

Our research group is mainly interested in cytokine induced signalling pathways related to allergic inflammation. The most prominent pro-allergic cytokine, mediating onset and progression of allergic diseases, is Interleukin 4 (IL-4). IL-4 drives the differentiation of a special subset of immune cells known as Th2 cells, which secrete a specific pattern of cytokines, and provide essential pro-allergic signals to the immune system. The main intracellular signalling cascade activated by IL-4 includes the transcription factor ‘Signal Transducer and Activator of Transcription 6 (STAT6)’. Data from STAT6 deficient mice show that STAT6 is one of the key players in allergic processes. Over the past years we, and others, have characterized a panel of genes regulated by STAT6. As expected, many of these genes are related to allergy. Interestingly, we recently found an interaction of IL-4/ STAT6 signalling with the Wnt signalling pathway. This pathway has previously been associated with embryogenesis and cancer. One of our current projects (sponsored by the FWF Project P18409-B13) concerns the molecular interaction of IL-4 regulated signalling molecules and transcription factors of the Wnt signalling pathway.

Another project focuses on the negative regulation of cytokine induced signalling by a family of inhibitory molecules known as Suppressors Of Cytokine Signalling (SOCS). SOCS proteins are able to interfere with the cytokine induced Jak/STAT signalling pathway by several mechanisms, thereby limiting the strength and duration of cytokine responses. Hence, SOCS proteins are regarded as potent inhibitors of cytokine mediated inflammatory responses including allergic diseases. Recent studies have shed some light on the role of SOCS proteins in dendritic cells (DC). Based on these findings we currently investigate molecular mechanisms responsible for the expression of SOCS proteins in DC, which act as key players in initiating immune responses.

In a recently initiated project, we deal with one of the latest discovered cytokines named IL-31. IL-31 was shown to be mainly secreted by Th2 cells, which makes it an interesting molecule in the context of allergic diseases. There are few data on biological functions of this new cytokine, but recent studies indicate that IL-31 is a potent mediator of inflammatory skin diseases like atopic dermatitis. In our project we will focus on the effects of IL-31 on DC, which are the most potent antigen presenting cells of the immune system.