Abstract
Phosphotyrosine phosphatases (PTPs) constitute a complex family of enzymes that control the balance of intracellular phosphorylation levels to allow cell responses while avoiding the development of diseases. Despite the relevance of CD4 T cell polarisation and effector function in human autoimmune diseases, the expression profile of PTPs during T helper polarisation and restimulation at inflammatory sites has not been assessed. Here, a systematic analysis of the expression profile of PTPs has been carried out during Th1-polarising conditions and upon PKC activation and intracellular raise of Ca2+ in effector cells. Changes in gene expression levels suggest a previously nonnoted regulatory role of several PTPs in Th1 polarisation and effector function. A substantial change in the spatial compartmentalisation of ERK during T cell responses is proposed based on changes in the dose of cytoplasmic and nuclear MAPK phosphatases. Our study also suggests a regulatory role of autoimmune-related PTPs in controlling T helper polarisation in humans. We expect that those PTPs that regulate T helper polarisation will constitute potential targets for intervening CD4 T cell immune responses in order to generate new therapies for the treatment of autoimmune diseases.
Highlights
CD4 T cells are important components of adaptive immune responses
Gene expression changes found in our study suggest the existence of previously nonnoted regulators of T helper 1 (Th1) polarisation and effector functions and, potential targets for the manipulation of CD4 T cell immune responses in future research directed to obtain therapies for the treatment of autoimmune diseases
PKC activation and cytosolic raise of Ca2+, induced by phorbol esters and Ionomycin (PI) treatment, mimic antigen stimulation via the T cell receptor (TCR) during T cell effector functions at inflammatory sites. By using this in vitro model, we studied the amount of mRNA, which indicates the dose of each protein tyrosine phosphatases (PTPs) in naıve and Th1 effector cells
Summary
CD4 T cells are important components of adaptive immune responses. During antigen stimulation, T cells polarise towards a type of effector cell specialised in controlling different sorts of infections by secreting different cytokines: Effector T helper 1 (Th1) secretes IFNγ and is specialised against intracellular pathogens, Th2 secretes IL-4 and is specialised against helminths, and Th17 secretes IL-17 and is specialised against extracellular bacterial and fungi. Catalytic activity of classes I to III is based on a Cysteine residue, while in the case of class IV it is based on an Aspartic acid residue [5, 6] Despite their important role in balancing phosphorylation levels, it is becoming clear that they regulate intracellular signalling by mechanisms not dependent on the phosphatase activity, including the competition for the binding of inhibitors, like in the case of phosphatase of regenerating liver-1 (PRL-1) [7], the control of the spatial regulation of nonphosphorylated substrates, like in the case of MAPK phosphatases (MKPs) [8], and the control of the catalytic activity of other PTPs, like in the case of noncatalytic myotubularins (MTMs) [9].
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