scholarly journals CD45 functions as a signaling gatekeeper in T cells

2019 ◽  
Vol 12 (604) ◽  
pp. eaaw8151 ◽  
Author(s):  
Adam H. Courtney ◽  
Alexey A. Shvets ◽  
Wen Lu ◽  
Gloria Griffante ◽  
Marianne Mollenauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tcr Signaling ◽  
Downstream Signaling ◽  
High Affinity ◽  
Signaling Events ◽  
Genetic Perturbations ◽  
Computational Analyses

T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling “gatekeeper,” enabling graded signaling outputs while filtering weak or spurious signaling events.

scholarly journals Shp1 regulates T cell homeostasis by limiting IL-4 signals

2013 ◽  
Vol 210 (7) ◽  
pp. 1419-1431 ◽  
Author(s):  
Dylan J. Johnson ◽  
Lily I. Pao ◽  
Salim Dhanji ◽  
Kiichi Murakami ◽  
Pamela S. Ohashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Tyrosine Phosphatase ◽  
Elevated Serum ◽  
Premature Death ◽  
Negative Regulator ◽  
T Cell Homeostasis ◽  
Tcr Signaling ◽  
Regulatory Molecule

The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell–intrinsic role of Shp1, we characterized mice with a T cell–specific Shp1 deletion (Shp1fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1fl/fl CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4+ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1-deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes.

912 Increased Expression of T Cell Protein Tyrosine Phosphatase (Tc-Ptp) PTPN2 by Mucosal T Cells in IBD Patients

2010 ◽  
Vol 138 (5) ◽  
pp. S-130
Author(s):  
Anja Schirbel ◽  
Jean-Paul Achkar ◽  
Florian Rieder ◽  
Manijeh Phillips ◽  
Gail West ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Protein ◽  
Protein Tyrosine ◽  
Mucosal T Cells

scholarly journals Dynamic regulation of CD45 by tetraspanin CD53

2019 ◽  
Author(s):  
V. E. Dunlock ◽  
A. B. Arp ◽  
E. Jansen ◽  
S. Charrin ◽  
S. J. van Deventer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Tyrosine Phosphatase ◽  
Adaptive Immune Response ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Dynamic Regulation ◽  
And Function

AbstractT cells are central to the adaptive immune response, playing a role in both the direct and indirect killing of pathogens and transformed cells. The activation of T cells is the result of a complex signaling cascade, initiated at the T cell receptor (TCR), and ending with the induction of proliferation. CD45, a member of the protein tyrosine phosphatase family, is one of the most abundant membrane proteins on T cells and functions by regulating activation directly downstream of the TCR. As a result of alternative splicing, CD45 can be expressed in multiple isoforms, naive T cells express the CD45RA isoform, while activated T cells gain expression of CD45RO, which has been proposed to increase signaling. Though the importance of CD45 in TCR signaling, proliferation and cytokine production is well established, little is known about the regulation of CD45 activity. We discovered that the immune-specific tetraspanin CD53 directly affects the stability and function of CD45RO in T cells.We have identified CD53 as a T cell co-stimulatory molecule in primary human and murine cells. Furthermore, we have shown that the absence of CD53 leads to an altered CD45 isoform expression as a result of decreased CD45RO stability on the cell surface. This instability was accompanied by increased mobility as measured by FRAP.Together, this indicates that CD53 functions as a stabilizer of CD45RO, and therefore as a positive regulator of TCR signaling at the T cell surface. Our data provides novel insight into the role of tetraspanins in the regulation of immune signaling and may provide a new avenue for the regulation of T cell signaling.

scholarly journals CD45 tyrosine phosphatase activity and membrane anchoring are required for T-cell antigen receptor signaling.

1994 ◽  
Vol 14 (12) ◽  
pp. 8078-8084 ◽  
Author(s):  
B B Niklinska ◽  
D Hou ◽  
C June ◽  
A M Weissman ◽  
J D Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phosphatase Activity ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Single Amino Acid ◽  
Tcr Signaling ◽  
Antigen Receptor Signaling ◽  
Membrane Anchoring

T cells that lack the CD45 transmembrane tyrosine phosphatase have a variety of T-cell receptor (TCR) signaling defects that are corrected by reexpression of wild-type CD45 or its intracytoplasmic domains. In this study, a chimeric molecule containing the myristylation sequence of Src and the intracellular portion of CD45, previously shown to restore function in CD45- T cells, was mutagenized to determine if membrane-associated CD45 tyrosine phosphatase activity is required to restore TCR-mediated signaling in CD45- T cells. Abolition of enzymatic activity by substitution of a serine for a critical cysteine in the first catalytic domain resulted in failure of this molecule to restore TCR signaling. Another mutation, in which a single amino acid substitution destroyed the myristylation site, resulted in failure of the chimeric molecule to partition to the plasma membrane. Although expressed at high levels and enzymatically active, this form of intracellular CD45 also failed to restore normal signaling in CD45- T cells. These findings strongly suggest that CD45's function in TCR signaling requires its proximity to membrane-associated tyrosine phosphatase substrates.

scholarly journals Lipid Raft Targeting of Hematopoietic Protein Tyrosine Phosphatase by Protein Kinase C θ-Mediated Phosphorylation

2006 ◽  
Vol 26 (5) ◽  
pp. 1806-1816 ◽  
Author(s):  
Konstantina Nika ◽  
Céline Charvet ◽  
Scott Williams ◽  
Lutz Tautz ◽  
Shane Bruckner ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Lipid Raft ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tcr Signaling ◽  
Immune Synapse ◽  
Protein Tyrosine ◽  
Kinase C

ABSTRACT Protein kinase C θ (PKC θ) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic protein tyrosine phosphatase (HePTP) also accumulates in the immune synapse in a PKC θ-dependent manner upon antigen recognition by T cells and is phosphorylated by PKC θ at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC θ−/− mice. In intact T cells, HePTP-S225A enhanced T-cell receptor (TCR)-induced NFAT/AP-1 transactivation, while the acidic substitution mutant was as efficient as wild-type HePTP. We conclude that HePTP is phosphorylated in the immune synapse by PKC θ and thereby targeted to lipid rafts to temper TCR signaling. This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling.

scholarly journals T Cell Receptor Engagement Leads to Phosphorylation of Clathrin Heavy Chain during Receptor Internalization

2004 ◽  
Vol 199 (7) ◽  
pp. 981-991 ◽  
Author(s):  
Victoria L. Crotzer ◽  
Allan S. Mabardy ◽  
Arthur Weiss ◽  
Frances M. Brodsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Heavy Chain ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Receptor Internalization ◽  
Tcr Signaling ◽  
Downstream Signaling ◽  
Clathrin Heavy Chain

T cell receptor (TCR) internalization by clathrin-coated vesicles after encounter with antigen has been implicated in the regulation of T cell responses. We demonstrate that TCR internalization after receptor engagement and TCR signaling involves inducible phosphorylation of clathrin heavy chain (CHC) in both CD4+ and CD8+ human T cells. Studies with mutant Jurkat T cells implicate the Src family kinase Lck as the responsible enzyme and its activity in this process is influenced by the functional integrity of the downstream signaling molecule ZAP-70. CHC phosphorylation positively correlates with ligand-induced TCR internalization in both CD4+ and CD8+ T cells, and CHC phosphorylation as a result of basal Lck activity is also implicated in constitutive TCR endocytosis by CD4+ T cells. Remarkably, irreversible CHC phosphorylation in the presence of pervanadate reduced both constitutive and ligand-induced TCR internalization in CD4+ T cells, and immunofluorescence studies revealed that this inhibition affected the early stages of TCR endocytosis from the plasma membrane. Thus, we propose that CHC phosphorylation and dephosphorylation are involved in TCR internalization and that this is a regulatory mechanism linking TCR signaling to endocytosis.

scholarly journals The roseoloviruses downregulate the protein tyrosine phosphatase PTPRC (CD45)

2020 ◽  
Author(s):  
Melissa L. Whyte ◽  
Kelsey Smith ◽  
Amanda Buchberger ◽  
Linda Berg Luecke ◽  
Lidya Handayani Tjan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Protein Tyrosine ◽  
Infected Cells

AbstractLike all herpesviruses, the roseoloviruses (HHV6A, -6B, and -7) establish lifelong infection within their host, requiring these viruses to evade host anti-viral responses. One common host-evasion strategy is the downregulation of host-encoded, surface-expressed glycoproteins. Roseoloviruses have been shown to evade host the host immune response by downregulating NK-activating ligands, MHC class I, and the TCR/CD3 complex. To more globally identify glycoproteins that are differentially expressed on the surface of HHV6A-infected cells, we performed cell surface capture of N-linked glycoproteins present on the surface of T cells infected with HHV6A, and compared these to proteins present on the surface of uninfected T cells. We found that the protein tyrosine phosphatase CD45 is downregulated in T cells infected with HHV6A. We also demonstrated that CD45 is similarly downregulated in cells infected with HHV-7. CD45 is essential for signaling through the T cell receptor and as such, is necessary for developing a fully functional immune response. Interestingly, the closely related β-herpesviruses human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) have also separately evolved unique mechanisms to target CD45. While HCMV and MCMV target CD45 signaling and trafficking, HHV6A acts to downregulate CD45 transcripts.ImportanceHuman herpesviruses-6 and -7 infect essentially 100% of the world’s population before the age of 5 and then remain latent or persistent in their host throughout life. As such, these viruses are among the most pervasive and stealthy of all viruses. Host immune cells rely on the presence of surface-expressed proteins to identify and target virus-infected cells. Here, we investigated the changes that occur to proteins expressed on the cell surface of T cells after infection with human herpesvirus-6A. We discovered that HHV-6A infection results in a reduction of CD45 on the surface of infected cells. Targeting of CD45 may prevent activation of these virus-infected T cells, possibly lengthening the life of the infected T cell so that it can harbor latent virus.

scholarly journals HIP-55 Is Important for T-Cell Proliferation, Cytokine Production, and Immune Responses

2005 ◽  
Vol 25 (16) ◽  
pp. 6869-6878 ◽  
Author(s):  
Jin Han ◽  
Jr-Wen Shui ◽  
Xuejun Zhang ◽  
Biao Zheng ◽  
Shuhua Han ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
T Cell Proliferation ◽  
Tcr Signaling ◽  
Signaling Events

ABSTRACT Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cγ1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.

scholarly journals The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling

2003 ◽  
Vol 162 (4) ◽  
pp. 673-682 ◽  
Author(s):  
Joseph Lin ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Phosphatase Domain ◽  
T Cell Clone ◽  
Immunologic Synapse

CD148 is a receptor-like protein tyrosine phosphatase up-regulated on T cells after T cell receptor (TCR) stimulation. To examine the physiologic role of CD148 in TCR signaling, we used an inducible CD148-expressing Jurkat T cell clone. Expression of CD148 inhibits NFAT (nuclear factor of activated T cells) activation induced by soluble anti-TCR antibody, but not by antigen-presenting cells (APCs) loaded with staphylococcal enterotoxin superantigen (SAg) or immobilized anti-TCR antibody. Immunofluorescence microscopy revealed that the extracellular domain of CD148 mediates its exclusion from the immunologic synapse, sequestering it from potential substrates. Targeting of the CD148 phosphatase domain to the immunologic synapse potently inhibited NFAT activation by all means of triggering through the TCR. These data lead us to propose a model where CD148 function is regulated in part by exclusion from substrates in the immunologic synapse. Upon T cell–APC disengagement, CD148 can then access and dephosphorylate substrates to down-regulate prolongation of signaling.

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