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Dynamic regulation of cytokine signalling in lymphocytes during inflammation

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Molecular dynamics of the immunological synapse

The immunological synapse (IS) of the lymphocytes integrates extracellular stimuli received by the network of surface receptors. A European project studied the molecular dynamics of IS formation.

Fundamental Research
Health

Tyrosine-specific protein phosphatases (PTP) catalyse the removal of a phosphate group attached to a tyrosine residue. These enzymes are key regulatory components in signal transduction pathways and cell cycle control. They are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity. The EU-funded project DCS (Dynamic regulation of cytokine signalling in lymphocytes during inflammation) studied the molecular dynamics of the signalling components at the IS. They also investigated the role of PTPs in lymphocyte activation and function. Additionally, researchers compared the expression of genes coding for PTPs in CD4+ T cells (helper cells of the immune system) of healthy donors as well as rheumatoid arthritis (RA) patients. The RA patients represented the autoimmunity model. Analysis of the expression profile of PTPs under Th1 polarisation and activation conditions, including cells derived from RA patients, showed a previously unknown regulation of the levels of several PTPs in CD4+ T cells. The study suggested a regulatory role of autoimmune-related PTPs in controlling T helper polarisation in humans. Thus, those PTPs that regulate T helper polarisation provide potential targets for new therapies for the treatment of autoimmune diseases. CD4+ T cells are thought to be involved in RA and researchers found changes in expression levels of certain genes in RA patients including the dual specific phosphatase DUSP7 and the cell cycle regulator CDC25B. Thus, the project established the basis for further investigation of the possible role of these PTPs as diagnostic biomarkers in clinical protocols. Another significant achievement was the dynamic distribution of certain PTPs to the IS. Gain and loss of function studies indicate a role of these proteins during T cell activation. In conclusion, project results help understanding of how signalling networks are regulated in immune cells, particularly, in the development of autoimmune diseases. Several PTPs have been found that are clearly regulated upon CD4+ T polarising conditions, suggesting new potential therapeutic targets.

Keywords

Immunological synapse, protein tyrosine phosphatases, DCS, CD4+ T cell, rheumatoid arthritis

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