Cytokines are key regulators of immune responses and inflammation. However, excessive pro-inflammatory cytokine stimulation promotes chronic inflammatory pathologies. Commonly used cytokine-neutralizing therapeutic drugs cause severe side effects and in some patients are not effective. We thus expect that study of the intracellular signalling triggered by cytokine stimulation will provide new, more selective and effective therapeutic targets. DCS will focus on human protein tyrosine phosphatases (PTP) and suppressors of cytokine signalling (SOCS), which are important regulators of immune cell function. Research on PTP is particularly relevant, due to the large number of these phosphatases expressed by lymphocytes and the unknown function of many of them in the cytokine signalling that affects lymphocyte activation in health and disease. Although intracellular phosphorylation levels are essential for normal lymphocyte activation while preventing disease, the significance of phosphorylated SOCS species in these processes is poorly understood, and the PTP that regulate their levels are unknown. We will thus initially determine PTP and SOCS expression profiles associated to rheumatoid arthritis (RA), as a model of an inflammatory disease. Once potential genes involved in the pathology are known, functional genomic approaches will be developed to screen PTP and SOCS for regulators of cytokine signalling during activation of T and NK cells, which are involved in inflammatory disease development. We will further screen PTP for regulators of SOCS phosphorylation to understand their role in lymphocyte activation. DCS will use advanced microspectroscopy techniques on live cells to study the molecular dynamics of cytokine signalling regulators at the T cell and NK cell immunological synapses. This dynamic local regulation is currently poorly understood, although it appears essential in determining lymphocyte differentiation and activation.
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