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Abstract
T cell activation and effector function is mediated by the formation of a long-lasting interaction established between T cells and antigen-presenting cells (APCs) called immunological synapse (IS). During T cell activation, different signaling molecules as well as the cytoskeleton and the endosomal compartment are polarized to the IS. This molecular dynamics is tightly regulated by phosphorylation networks, which are controlled by protein tyrosine phosphatases (PTPs). While some PTPs are known to be important regulators of adhesion, ligand discrimination or the stimulation threshold, there is still little information about the regulatory role of PTPs in cytoskeleton rearrangements and endosomal compartment dynamics. Besides, spatial and temporal regulation of PTPs and substrates at the IS is only barely known. Consistent with an important role of PTPs in T cell activation, multiple mutations as well as altered expression levels or dynamic behaviors have been associated with autoimmune diseases. However, the precise mechanism for the regulation of T cell activation and effector function by PTPs in health and autoimmunity is not fully understood. Herein, we review the current knowledge about the regulatory role of PTPs in CD4+ T cell activation, IS assembly and effector function. The potential molecular mechanisms mediating the action of these enzymes in autoimmune disorders are discussed.
Highlights
Tight regulation of intracellular phosphorylation networks by kinase and phosphatase activities mediates cellular responses and prevents pathological disorders
Supporting an important coordinated role of protein tyrosine phosphatases (PTPs) during T cell immune responses, we have recently shown a regulated expression of a high percentage of PTPs during human CD4+ T cell polarization and Th1 effector function [29]
SSU72 overexpression reduces STAT3 signaling, Th17 differentiation, IL-17 production, and the incidence and severity of collageninduced arthritis (CIA), while attenuated expression of this phosphatase is found in CD4+ T cells of rheumatoid arthritis (RA) patients, likely due to hypermethylation of the gene [81]
Summary
Tight regulation of intracellular phosphorylation networks by kinase and phosphatase activities mediates cellular responses and prevents pathological disorders. In 2004, Alonso and co-workers postulated that 107 human genes code for protein tyrosine phosphatases (PTPs), characterized by conserved catalytic motifs and phosphatase domains [1]. The superfamily of PTPs has recently been increased to 125 members, the so-called extended PTPome [2] (Figure 1 and Box 1). In addition to enzymes specific for phospho-Tyrosine (pTyr) residues, certain PTPs are able to dephosphorylate phospho-Serine (pSer) and phospho-Threonine (pThr) residues, phospholipids, or mRNA [1, 2]
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