Regulation of TCR signalling by tyrosine phosphatases: from immune homeostasis to autoimmunity

Abstract

Activation of T cells is largely mediated through signal transduction downstream from the T-cell receptor (TCR) expressed on the cell surface. The TCR is a transmembrane receptor complex comprised of a and b chains, which bind ligands, and CD3 (e, c and d) and f chains containing motifs that are phosphorylated on tyrosine, called immunoreceptor tyrosine-based activation motifs. Signal transduction through the TCR is initiated when the receptor binds to a peptide-MHC complex presented by an antigen-presenting cell. This interaction initiates a cascade of signalling events, which induces the proliferation, mobilization and differentiation of T cells. For an updated and comprehensive review of signalling through the TCR the reader is referred to recent authoritative publications. [1][2][3][4] A dynamic wave of tyrosine phosphorylation phenomena is critical for ignition of intracellular signalling in T cells. Engagement of the TCR leads to the activation of the Src family protein tyrosine kinases (PTKs) LCK and FYN, which phosphorylate the immunoreceptor tyrosinebased activation motifs of the TCR. This provides docking sites for the SH2 domains of ZAP-70, a Syk family PTK, allowing ZAP-70 to be phosphorylated and activated by LCK. Once activated, ZAP-70 phosphorylates the adaptor proteins SLP-76 and LAT, which nucleate signalling complexes, leading to the phosphorylation and activation of multiple downstream effectors. This results in calcium mobilization, activation of mitogen-activated protein kinases (MAPKs), transcriptional regulation and cytoskeletal rearrangements.Protein tyrosine phosphatases (PTPs) are the natural counterpart of PTKs. Much like PTKs, depending upon the phosphorylation site and the signalling context, they can enhance or reduce the function of their protein target(s). The modern view of phosphorylation networks is one of dynamic 'always-on' grids where the stoichiometry of each phosphorylation site is continuously controlled by the changing balance between the activities of kinases and phosphatases. For example, the activation state of the Src family kinases (SFKs) is balanced between the activities of CSK and CD45, which respectively phosphorylate and dephosphorylate the inhibitory C-terminal site (Y505 of LCK), and the negative regulators LYP and SHP-1, which dephosphorylate an activating tyrosine in the catalytic domain (Y394 of LCK). Acute changes in PTP activity/ expression are in principle sufficient to alter the network status and even trigger true signalling waves. The recent 'kinetic-segregation' model postulates that PTPs are responsible for the very initiation of signalling after engagement of the TCR. SummaryMore than half of the known protein tyrosine phosphatases (PTPs) in the human genome are expressed in T cells, and significant progress has been made in elucidating the biology of these enzymes in T-cell development and function. Here we provide a systematic review of the current understanding of the roles of PTPs in T-cell activation, providing insight into their mechanisms ...

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

“…Examples of such dysregulations, including defective Lck, have been reported. 8,20,[59][60][61] Our results implicate another intracellular target (DUSP4) in these impaired TCR responses. DUSP4 silencing improved ICL TCR signaling in vitro and increased CD27 and CD40L expressions, which is likely to be consistent with the ability of DUSP4 knockdown to restore T-cell-dependent B-cell responses.…”

Single-cell mass cytometry of TCR signaling: Amplification of small initial differences results in low ERK activation in NOD mice

“…These observations suggest that some CD3ζ subunits may be sequestered or not available to participate in functional signalosomes, a hypothesis in agreement with earlier reports showing that NOD T cells have an excess of free CD3ζ chains on the plasma membrane (15). Alternatively, regulatory phosphatases like PTPN22, which has genetic variants that are linked to several autoimmune diseases (21), could constrain CD3ζ phosphorylation in NOD cells.…”

T-cell protein tyrosine phosphatase (TCPTP) regulates phosphorylation of Txk, a tyrosine kinase of the Tec family

“…Class I, or classical PTPs, consist of receptor and non-receptor type PTPs, of which the vast majority of non-receptor type PTP are expressed in the cytosol 6,7) .…”