scholarly journals Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Interferes with Extracellular Signal-regulated Kinase (ERK) and Jun NH2-terminal Kinase (JNK) Activation, but Does Not Affect Phosphorylation of T Cell Receptor ζ and ZAP70

1997 ◽  
Vol 186 (10) ◽  
pp. 1645-1653 ◽  
Author(s):  
Concepcion Revilla Calvo ◽  
Derk Amsen ◽  
Ada M. Kruisbeek
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Lymphocyte Antigen ◽  
Extracellular Signal ◽  
Signaling Events

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-ζ chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.

scholarly journals Ligation of Cytotoxic T Lymphocyte Antigen-4 to T Cell Receptor Inhibits T Cell Activation and Directs Differentiation into Foxp3+Regulatory T Cells

2012 ◽  
Vol 287 (14) ◽  
pp. 11098-11107 ◽  
Author(s):  
Jozsef Karman ◽  
Ji-Lei Jiang ◽  
Nathan Gumlaw ◽  
Hongmei Zhao ◽  
Juanita Campos-Rivera ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocyte Antigen

CTLA-4 blockade of antigen-induced cell death

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1134-1137 ◽  
Author(s):  
Silvy da Rocha Dias ◽  
Christopher E. Rudd
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Single Mutation ◽  
Fasl Expression ◽  
Tcr Signaling

Abstract While cytotoxic T lymphocyte antigen–4 (CTLA-4) negatively regulates T-cell receptor (TCR)–driven interleukin (IL)–2 production and proliferation, little is known regarding whether the coreceptor has the capacity to inhibit other events, such as Fas ligand (FasL) expression and antigen-induced cell death (AICD). In this study, it is shown that CTLA-4 expressed in a T-cell hybridoma can elicit a potent block of FasL expression and AICD. Inhibition occurred independently of CTLA-4 blockage of IL-2 production and was partially reversed by a single mutation in the cytoplasmic YVKM motif. These findings indicate that CTLA-4 can block TCR signaling prior to bifurcation of signals leading to IL-2 production and apoptosis.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

scholarly journals Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17

2004 ◽  
Vol 279 (50) ◽  
pp. 52762-52771 ◽  
Author(s):  
Xikui K. Liu ◽  
Xin Lin ◽  
Sarah L. Gaffen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Promoter Activity ◽  
Cell Receptor ◽  
Cross Linking ◽  
Supporting Evidence ◽  
Nuclear Factor ◽  
Tcr Signaling ◽  
Activated T Cells

The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To definecis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative promoter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal promoter, we created a series of 5′ truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this regionin vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter.

scholarly journals Differential T cell receptor photoaffinity labeling among H-2Kd restricted cytotoxic T lymphocyte clones specific for a photoreactive peptide derivative. Labeling of the alpha-chain correlates with J alpha segment usage.

1993 ◽  
Vol 177 (5) ◽  
pp. 1247-1256 ◽  
Author(s):  
P Romero ◽  
J L Casanova ◽  
J C Cerottini ◽  
J L Maryanski ◽  
I F Luescher
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Photoaffinity Labeling ◽  
Cell Receptor ◽  
Tryptophan Residue ◽  
Alpha Chain ◽  
Peptide Derivative ◽  
Specificity Pattern

Using a direct binding assay based on photoaffinity labeling, we studied the interaction of T cell receptor (TCR) with a Kd-bound photoreactive peptide derivative on living cells. The Kd-restricted Plasmodium berghei circumsporozoite (PbCS) peptide 253-260 (YIPSAEKI) was reacted NH2-terminally with biotin and at the TCR contact residue Lys259 with photoreactive iodo, 4-azido salicylic acid (IASA) to make biotin-YIPSAEK(IASA)I. Cytotoxic T lymphocyte (CTL) clones derived from mice immunized with this derivative recognized this conjugate, but not a related one lacking the IASA group nor the parental PbCS peptide. The clones were Kd restricted. Recognition experiments with variant conjugates, lacking substituents from IASA, revealed a diverse fine specificity pattern and indicated that this group interacted directly with the TCR. The TCR of four clones could be photoaffinity labeled by biotin-YIPSAEK(125IASA)I. This labeling was dependent on the conjugates binding to the Kd molecule and was selective for the TCR alpha (2 clones) or beta chain (1 clone), or was common for both chains (1 clone). TCR sequence analysis showed a preferential usage of J alpha TA28 containing alpha chains that were paired with V beta 1 expressing beta chains. The TCR that were photoaffinity labeled at the alpha chain expressed these J alpha and V beta segments. The tryptophan encoded by the J alpha TA28 segment is rarely found in other J alpha segments. Moreover, we show that the IASA group interacts preferentially with tryptophan in aqueous solution. We thus propose that for these CTL clones, labeling of the alpha chain occurs via the J alpha-encoded tryptophan residue.

scholarly journals Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties

2007 ◽  
Vol 282 (33) ◽  
pp. 23799-23810 ◽  
Author(s):  
Bruno Laugel ◽  
Hugo A. van den Berg ◽  
Emma Gostick ◽  
David K. Cole ◽  
Linda Wooldridge ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocyte Activation ◽  
Cell Receptor ◽  
Binding Properties ◽  
Receptor Affinity ◽  
Tetramer Binding ◽  
T Lymphocyte Activation

scholarly journals Distinct T cell receptor signaling requirements for perforin- or FasL-mediated cytotoxicity.

1996 ◽  
Vol 183 (4) ◽  
pp. 1697-1706 ◽  
Author(s):  
M T Esser ◽  
B Krishnamurthy ◽  
V L Braciale
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
T Cell Receptor ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Tcr Signaling

A diverse array of signals are generated in a cytotoxic T lymphocyte (CTL) after the T cell receptor (TCR) engages the class I major histocompatibility complex (MHC) peptide complex. These signals result in a multitude of CTL effector functions, including cellular cytotoxicity, cell surface receptor expression, and cytokine secretion. We have examined signaling through the TCR in a wild type CD8+, MHC-restricted, antigen-specific CTL clone, 14-7, and its interleukin 2-dependent variant clone 14-7FD. We report here that 14-7FD is unable to kill via the perforin mechanism of killing, yet is able to kill via the Fas ligand/Fas mechanism and secrete interferon-gamma in an antigen-specific manner. 14-7FD has cytolytic granules that contain perforin and serine esterases, which are secreted after phorbol ester and Ca2+ ionophore treatment. Lastly, to investigate which TCR signaling requirements were operational in 14-7FD, we examined TCR-triggered intracellular Ca2+ mobilization in the two clones. After TCR engagement, 14-7FD failed to mobilize intracellular Ca2+, which may be the cause for its inability to trigger the perforin/granule exocytosis mechanism of killing. These results indicate that the signal transduction events that trigger perforin killing and the signaling requirements to induce FasL expression are distinct. We hypothesize that these two distinct TCR signal transduction requirements allow for separate activation of these two mechanisms of killing relating to their role in eradication of infected cells or regulation of immune responses.

T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A

1994 ◽  
Vol 24 (10) ◽  
pp. 2469-2476 ◽  
Author(s):  
Alberto Anel ◽  
Michel Buferne ◽  
Claude Boyer ◽  
Anne-Marie Schmitt-Verhulst ◽  
Pierre Golstein
Keyword(s):  
T Cell ◽  
Cyclosporin A ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Protein Tyrosine Kinase ◽  
Fas Ligand ◽  
Kinase Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Ligand Expression
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