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.

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.

Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor

1994 ◽  
Vol 14 (2) ◽  
pp. 1095-1103
Author(s):  
A L Burkhardt ◽  
T Costa ◽  
Z Misulovin ◽  
B Stealy ◽  
J B Bolen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Cell Antigen

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

scholarly journals T Cell Receptor–initiated Calcium Release Is Uncoupled from Capacitative Calcium Entry in Itk-deficient T Cells

1998 ◽  
Vol 187 (10) ◽  
pp. 1721-1727 ◽  
Author(s):  
Karen-Qianye Liu ◽  
Stephen C. Bunnell ◽  
Christine B. Gurniak ◽  
Leslie J. Berg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Calcium Release ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Calcium Entry ◽  
Tcr Signaling ◽  
Store Depletion ◽  
High Concentrations

Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk−/− T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk−/− T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C γ1 tyrosine phosphorylation are substantially reduced in Itk−/− T cells. In contrast, TCR-ζ and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium.

scholarly journals Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor αβ lineage

1998 ◽  
Vol 95 (16) ◽  
pp. 9459-9464 ◽  
Author(s):  
Stephanie T. Page ◽  
Lisa Y. Bogatzki ◽  
Jessica A. Hamerman ◽  
Claire H. Sweenie ◽  
Philip J. Hogarth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Nude Mice ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Tcr Signaling ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Cell Commitment

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically. The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) αβ- and γδ-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8α homodimer. In addition, they can utilize the Fc receptor γ-chain in place of the CD3-associated ζ-chain for TCR signaling and their maturation depends on the interleukin 2 receptor β-chain. Moreover, TCRαβ+CD8αα+ IEL are not subject to conventional thymic selection processes. To determine whether CD3−CD8αα+ IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3ɛ, or both Lck and Fyn, in which thymic T cell development is arrested. CD3−CD8αα+CD16+ IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRα transcripts, a marker of T cell commitment. These IEL from lck−/−fyn−/− animals exhibited TCR β-gene rearrangement. However, CD3−CD8αα+CD16+ IEL from ɛ-deficient mice had not undergone Dβ-Jβ joining, despite normal rearrangement at the TCRβ locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3ɛ in IEL maturation.

scholarly journals Dynamic palmitoylation events following T-cell receptor signaling

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Eliot Morrison ◽  
Tatjana Wegner ◽  
Andres Ernesto Zucchetti ◽  
Miguel Álvaro-Benito ◽  
Ashley Zheng ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
Tcr Signaling ◽  
T Cell Receptor Signaling ◽  
Cell Receptor Signaling

AbstractPalmitoylation is the reversible addition of palmitate to cysteine via a thioester linkage. The reversible nature of this modification makes it a prime candidate as a mechanism for regulating signal transduction in T-cell receptor signaling. Following stimulation of the T-cell receptor we find a number of proteins are newly palmitoylated, including those involved in vesicle-mediated transport and Ras signal transduction. Among these stimulation-dependent palmitoylation targets are the v-SNARE VAMP7, important for docking of vesicular LAT during TCR signaling, and the largely undescribed palmitoyl acyltransferase DHHC18 that is expressed in two isoforms in T cells. Using our newly developed On-Plate Palmitoylation Assay (OPPA), we show DHHC18 is capable of palmitoylating VAMP7 at Cys183. Cellular imaging shows that the palmitoylation-deficient protein fails to be retained at the Golgi and to localize to the immune synapse upon T cell activation.

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.

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

scholarly journals Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation

2002 ◽  
Vol 195 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Satish Devadas ◽  
Luba Zaritskaya ◽  
Sue Goo Rhee ◽  
Larry Oberley ◽  
Mark S. Williams
Keyword(s):  
Hydrogen Peroxide ◽  
T Cell ◽  
T Cell Receptor ◽  
Superoxide Anion ◽  
Fas Ligand ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Tcr Signals ◽  
Hydrogen Peroxide Generation

Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of all ROS. Anti-CD3 induced phosphorylation of extracellular signal–regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK).

scholarly journals Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor.

1994 ◽  
Vol 14 (2) ◽  
pp. 1095-1103 ◽  
Author(s):  
A L Burkhardt ◽  
T Costa ◽  
Z Misulovin ◽  
B Stealy ◽  
J B Bolen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Antigen Receptors ◽  
Cell Antigen

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

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