Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Science 24 July 1998:
Vol. 281. no. 5376, pp. 572 - 575
DOI: 10.1126/science.281.5376.572

Reports

Fidelity of T Cell Activation Through Multistep T Cell Receptor zeta  Phosphorylation

Ellen Neumeister Kersh, Andrey S. Shaw, Paul M. Allen *

The T cell receptor (TCR) alpha beta heterodimer interacts with its ligands with high specificity, but surprisingly low affinity. The role of the zeta  component of the murine TCR in contributing to the fidelity of antigen recognition was examined. With sequence-specific phosphotyrosine antibodies, it was found that zeta  undergoes a series of ordered phosphorylation events upon TCR engagement. Completion of phosphorylation steps is dependent on the nature of the TCR ligand. Thus, the phosphorylation steps establish thresholds for T cell activation. This study documents the sophisticated molecular events that follow the engagement of a low-affinity receptor.

Center for Immunology and Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
*   To whom correspondence should be addressed. E-mail: allen{at}immunology.wustl.edu


Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
(-)-Epigallocatechin Gallate Regulates CD3-mediated T Cell Receptor Signaling in Leukemia through the Inhibition of ZAP-70 Kinase.
J.-H. Shim, H. S. Choi, A. Pugliese, S.-Y. Lee, J.-I. Chae, B. Y. Choi, A. M. Bode, and Z. Dong (2008)
J. Biol. Chem. 283, 28370-28379
   Abstract »    Full Text »    PDF »
Direct and Indirect Interactions of the Cytoplasmic Region of CD244 (2B4) in Mice and Humans with FYN Kinase.
N. G. Clarkson, S. J. Simmonds, M. J. Puklavec, and M. H. Brown (2007)
J. Biol. Chem. 282, 25385-25394
   Abstract »    Full Text »    PDF »
The Constitutive Tyrosine Phosphorylation of CD3{zeta} Results from TCR-MHC Interactions That Are Independent of Thymic Selection.
A. M. Becker, L. M. DeFord-Watts, C. Wuelfing, and N. S. C. van Oers (2007)
J. Immunol. 178, 4120-4128
   Abstract »    Full Text »    PDF »
Mitogenic CD28 Signals Require the Exchange Factor Vav1 to Enhance TCR Signaling at the SLP-76-Vav-Itk Signalosome.
K. M. Dennehy, F. Elias, S.-Y. Na, K.-D. Fischer, T. Hunig, and F. Luhder (2007)
J. Immunol. 178, 1363-1371
   Abstract »    Full Text »    PDF »
Defining Yourself: Tolerance Development in the Immune System.
P. M. Allen (2006)
J. Immunol. 177, 1369-1372
   Full Text »    PDF »
Rules for Modeling Signal-Transduction Systems.
W. S. Hlavacek, J. R. Faeder, M. L. Blinov, R. G. Posner, M. Hucka, and W. Fontana (2006)
Sci. STKE 2006, re6
   Abstract »    Full Text »    PDF »
Binding of multivalent CD147 phage induces apoptosis of U937 cells.
N. Intasai, S. Mai, W. Kasinrerk, and C. Tayapiwatana (2006)
Int. Immunol. 18, 1159-1169
   Abstract »    Full Text »    PDF »
Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs).
C. P. Swaminathan, P. H. Brown, A. Roychowdhury, Q. Wang, R. Guan, N. Silverman, W. E. Goldman, G.-J. Boons, and R. A. Mariuzza (2006)
PNAS 103, 684-689
   Abstract »    Full Text »    PDF »
Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function.
K. S. Weber, D. L. Donermeyer, P. M. Allen, and D. M. Kranz (2005)
PNAS 102, 19033-19038
   Abstract »    Full Text »    PDF »
Metal-on-Metal Bearings and Hypersensitivity in Patients with Artificial Hip Joints. A Clinical and Histomorphological Study.
H.-G. Willert, G. H. Buchhorn, A. Fayyazi, R. Flury, M. Windler, G. Koster, and C. H. Lohmann (2005)
J. Bone Joint Surg. Am. 87, 28-36
   Abstract »    Full Text »    PDF »
Functional Reprogramming of the Primary Immune Response by T Cell Receptor Antagonism.
D. Haribhai, B. Edwards, M. L. Williams, and C. B. Williams (2004)
J. Exp. Med. 200, 1371-1382
   Abstract »    Full Text »    PDF »
Qualitatively differential regulation of T cell activation and apoptosis by T cell receptor {zeta} chain ITAMs and their tyrosine residues.
W.-J. Chae, H.-K. Lee, J.-H. Han, S.-W. V. Kim, A. L.M. Bothwell, T. Morio, and S.-K. Lee (2004)
Int. Immunol. 16, 1225-1236
   Abstract »    Full Text »    PDF »
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules.
M. P. Mycko, H. Waldner, D. E. Anderson, K. D. Bourcier, K. W. Wucherpfennig, V. K. Kuchroo, and D. A. Hafler (2004)
J. Immunol. 173, 1689-1698
   Abstract »    Full Text »    PDF »
Recognition of Variant HIV-1 Epitopes from Diverse Viral Subtypes by Vaccine-Induced CTL.
D. M. McKinney, R. Skvoretz, B. D. Livingston, C. C. Wilson, M. Anders, R. W. Chesnut, A. Sette, M. Essex, V. Novitsky, and M. J. Newman (2004)
J. Immunol. 173, 1941-1950
   Abstract »    Full Text »    PDF »
CD38 Signaling in T Cells Is Initiated within a Subset of Membrane Rafts Containing Lck and the CD3-{zeta} Subunit of the T Cell Antigen Receptor.
P. Munoz, M.-d.-C. Navarro, E. J. Pavon, J. Salmeron, F. Malavasi, J. Sancho, and M. Zubiaur (2003)
J. Biol. Chem. 278, 50791-50802
   Abstract »    Full Text »    PDF »
Recombinant TCR Ligand Induces Early TCR Signaling and a Unique Pattern of Downstream Activation.
C. Wang, J. L. Mooney, R. Meza-Romero, Y. K. Chou, J. Huan, A. A. Vandenbark, H. Offner, and G. G. Burrows (2003)
J. Immunol. 171, 1934-1940
   Abstract »    Full Text »    PDF »
T Cell Antagonism is Functionally Uncoupled from the 21- and 23-kDa Tyrosine-Phosphorylated TCR {zeta} Subunits.
L. A. Pitcher, P. S. Ohashi, and N. S. C. van Oers (2003)
J. Immunol. 171, 845-852
   Abstract »    Full Text »    PDF »
Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function.
D.-G. Lim, J. M. Slavik, K. Bourcier, K. J. Smith, and D. A. Hafler (2003)
J. Exp. Med. 198, 99-109
   Abstract »    Full Text »    PDF »
The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities.
S. L. Hutchinson, L. Wooldridge, S. Tafuro, B. Laugel, M. Glick, J. M. Boulter, B. K. Jakobsen, D. A. Price, and A. K. Sewell (2003)
J. Biol. Chem. 278, 24285-24293
   Abstract »    Full Text »    PDF »
Cutting Edge: Dependence of TCR Antagonism on Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Activity.
N. E. Kilgore, J. D. Carter, U. Lorenz, and B. D. Evavold (2003)
J. Immunol. 170, 4891-4895
   Abstract »    Full Text »    PDF »
Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry.
A. R. Salomon, S. B. Ficarro, L. M. Brill, A. Brinker, Q. T. Phung, C. Ericson, K. Sauer, A. Brock, D. M. Horn, P. G. Schultz, et al. (2003)
PNAS 100, 443-448
   Abstract »    Full Text »    PDF »
Induction of the Early Growth Response Gene 1 Promoter by TCR Agonists and Partial Agonists: Ligand Potency Is Related to Sustained Phosphorylation of Extracellular Signal-Related Kinase Substrates.
H. Xi and G. J. Kersh (2003)
J. Immunol. 170, 315-324
   Abstract »    Full Text »    PDF »
Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity.
J. Tian, A. P. Olcott, and D. L. Kaufman (2002)
J. Immunol. 169, 6564-6569
   Abstract »    Full Text »    PDF »
Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non-Self-Ligand.
M. Munder, E. Bettelli, L. Monney, J. M. Slavik, L. B. Nicholson, and V. K. Kuchroo (2002)
J. Exp. Med. 196, 1151-1162
   Abstract »    Full Text »    PDF »
Positive Selection by the Pre-TCR Yields Mature CD8+ T Cells.
Y. Ito, S. Arai, N. S. C. van Oers, I. Aifantis, H. von Boehmer, and T. Miyazaki (2002)
J. Immunol. 169, 4913-4919
   Abstract »    Full Text »    PDF »
TCR/CD3 Down-Modulation and {zeta} Degradation Are Regulated by ZAP-70.
C. Dumont, N. Blanchard, V. Di Bartolo, N. Lezot, E. Dufour, S. Jauliac, and C. Hivroz (2002)
J. Immunol. 169, 1705-1712
   Abstract »    Full Text »    PDF »
Development of CD25+ T cells secreting transforming growth factor-{beta}1 by altered peptide ligands expressed as self-antigens.
H. Yamashiro, N. Hozumi, and N. Nakano (2002)
Int. Immunol. 14, 857-865
   Abstract »    Full Text »    PDF »
TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells.
E. N. Kersh, S. M. Kaech, T. M. Onami, M. Moran, E. J. Wherry, M. C. Miceli, and R. Ahmed (2002)
J. Immunol. 170, 5455-5463
   Abstract »    Full Text »    PDF »
The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor.
C. A. Chambers, J. Kang, Y. Wu, W. Held, D. H. Raulet, and J. P. Allison (2002)
Blood 99, 4509-4516
   Abstract »    Full Text »    PDF »
A VH12 Transgenic Mouse Exhibits Defects in Pre-B Cell Development and Is Unable to Make IgM+ B Cells.
H. Wang, J. Ye, L. W. Arnold, S. K. McCray, and S. H. Clarke (2001)
J. Immunol. 167, 1254-1262
   Abstract »    Full Text »    PDF »
A T Cell Clone's Avidity Is a Function of Its Activation State.
M. D. Hesse, A. Y. Karulin, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann (2001)
J. Immunol. 167, 1353-1361
   Abstract »    Full Text »    PDF »
The Frequency of High Avidity T Cells Determines the Hierarchy of Determinant Spreading.
J. Tian, S. Gregori, L. Adorini, and D. L. Kaufman (2001)
J. Immunol. 166, 7144-7150
   Abstract »    Full Text »    PDF »
Prolonged Exposure of T Cells to TNF Down-Regulates TCR{{zeta}} and Expression of the TCR/CD3 Complex at the Cell Surface.
P. Isomaki, M. Panesar, A. Annenkov, J. M. Clark, B. M. J. Foxwell, Y. Chernajovsky, and A. P. Cope (2001)
J. Immunol. 166, 5495-5507
   Abstract »    Full Text »    PDF »
Glucocorticoids Attenuate T Cell Receptor Signaling.
F. Van Laethem, E. Baus, L. A. Smyth, F. Andris, F. Bex, J. Urbain, D. Kioussis, and O. Leo (2001)
J. Exp. Med. 193, 803-814
   Abstract »    Full Text »    PDF »
Monocytes Are Differentially Activated Through HLA-DR, -DQ, and -DP Molecules Via Mitogen-Activated Protein Kinases.
T. Matsuoka, H. Tabata, and S. Matsushita (2001)
J. Immunol. 166, 2202-2208
   Abstract »    Full Text »    PDF »
Combinatorial Effect of T-Cell Receptor Ligation and CD45 Isoform Expression on the Signaling Contribution of the Small GTPases Ras and Rap1.
J. Czyzyk, D. Leitenberg, T. Taylor, and K. Bottomly (2000)
Mol. Cell. Biol. 20, 8740-8747
   Abstract »    Full Text »
Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells.
P. A. Carpenter, S. Pavlovic, J. Y. Tso, O. W. Press, T. Gooley, X.-Z. Yu, and C. Anasetti (2000)
J. Immunol. 165, 6205-6213
   Abstract »    Full Text »    PDF »
Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients.
S. Nervi, C. Atlan-Gepner, B. Kahn-Perles, P. Lecine, B. Vialettes, J. Imbert, and P. Naquet (2000)
J. Immunol. 165, 5874-5883
   Abstract »    Full Text »    PDF »
Function of Cd3{varepsilon}-Mediated Signals in T Cell Development.
C. L. Sommers, J. B. Dejarnette, K. Huang, J. Lee, D. El-Khoury, E. W. Shores, and P. E. Love (2000)
J. Exp. Med. 192, 913-920
   Abstract »    Full Text »    PDF »
Fully competent dendritic cells as inducers of T cell anergy in autoimmunity.
S. Quaratino, L. P. Duddy, and M. Londei (2000)
PNAS
   Abstract »    Full Text »
CD81 and CD28 Costimulate T Cells Through Distinct Pathways.
D. A. Witherden, R. Boismenu, and W. L. Havran (2000)
J. Immunol. 165, 1902-1909
   Abstract »    Full Text »    PDF »
Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo.
Y. Peng, E. Falck-Pedersen, and K. B. Elkon (2000)
J. Immunol. 165, 1470-1478
   Abstract »    Full Text »    PDF »
A self-hsp60 peptide acts as a partial agonist inducing expression of B7-2 on mycobacterial hsp60-specific T cells: a possible mechanism for inhibitory T cell regulation of adjuvant arthritis?.
A. G. A. Paul, R. van der Zee, L. S. Taams, and W. van Eden (2000)
Int. Immunol. 12, 1041-1050
   Abstract »    Full Text »    PDF »
Ligand-Specific Selection of MHC Class II-Restricted Thymocytes in Fetal Thymic Organ Culture.
G. J. Kersh, D. L. Engle, C. B. Williams, and P. M. Allen (2000)
J. Immunol. 164, 5675-5682
   Abstract »    Full Text »    PDF »
The T-Cell Receptor zeta Chain Contains Two Homologous Domains with Which Simian Immunodeficiency Virus Nef Interacts and Mediates Down-Modulation.
T. M Schaefer, I. Bell, B. A. Fallert, and T. A. Reinhart (2000)
J. Virol. 74, 3273-3283
   Abstract »    Full Text »
A Population of In Vivo Anergized T Cells with a Lower Activation Threshold for the Induction of CD25 Exhibit Differential Requirements in Mobilization of Intracellular Calcium and Mitogen-Activated Protein Kinase Activation.
O. Utting, S.-J. Teh, and H.-S. Teh (2000)
J. Immunol. 164, 2881-2889
   Abstract »    Full Text »    PDF »
T-Cell Receptor-Mediated Anergy of a Human Immunodeficiency Virus (HIV) gp120-Specific CD4+ Cytotoxic T-Cell Clone, Induced by a Natural HIV Type 1 Variant Peptide.
L. Bouhdoud, P. Villain, A. Merzouki, M. Arella, and C. Couture (2000)
J. Virol. 74, 2121-2130
   Abstract »    Full Text »
Sequential Requirements of the N-Terminal Palmitoylation Site and SH2 Domain of Src Family Kinases in the Initiation and Progression of Fcvarepsilon RI Signaling.
Z.-i. Honda, T. Suzuki, H. Kono, M. Okada, T. Yamamoto, C. Ra, Y. Morita, and K. Yamamoto (2000)
Mol. Cell. Biol. 20, 1759-1771
   Abstract »    Full Text »
Differential T-Cell Antigen Receptor Signaling Mediated by the Src Family Kinases Lck and Fyn.
M. F. Denny, B. Patai, and D. B. Straus (2000)
Mol. Cell. Biol. 20, 1426-1435
   Abstract »    Full Text »
Single-Cytokine-Producing CD4 Memory Cells Predominate in Type 1 and Type 2 Immunity.
A. Y. Karulin, M. D. Hesse, M. Tary-Lehmann, and P. V. Lehmann (2000)
J. Immunol. 164, 1862-1872
   Abstract »    Full Text »    PDF »
Tetracycline-controllable Selection of CD4+ T Cells: Half-Life and Survival Signals in the Absence of Major Histocompatibility Complex Class II Molecules.
D. Witherden, N. van Oers, C. Waltzinger, A. Weiss, C. Benoist, and D. Mathis (2000)
J. Exp. Med. 191, 355-364
   Abstract »    PDF »
Partially Phosphorylated T Cell Receptor {zeta} Molecules Can Inhibit T Cell Activation.
E. N. Kersh, G. J. Kersh, and P. M. Allen (1999)
J. Exp. Med. 190, 1627-1636
   Abstract »    Full Text »    PDF »
Differential Requirements for NF-{kappa}B and AP-1 trans-Activation in Response to Minimal TCR Engagement by a Partial Agonist in Naive CD8 T Cells.
N. Auphan, S. Ghosh, R. A. Flavell, and A.-M. Schmitt-Verhulst (1999)
J. Immunol. 163, 5219-5227
   Abstract »    Full Text »    PDF »
Differential Requirements for CD4 in TCR-Ligand Interactions.
K. Vidal, C. Daniel, M. Hill, D. R. Littman, and P. M. Allen (1999)
J. Immunol. 163, 4811-4818
   Abstract »    Full Text »    PDF »
Thermodynamics of T cell receptor binding to peptide-MHC: Evidence for a general mechanism of molecular scanning.
J. J. Boniface, Z. Reich, D. S. Lyons, and M. M. Davis (1999)
PNAS 96, 11446-11451
   Abstract »    Full Text »    PDF »
Translocation of tyrosine-phosphorylated TCR{zeta} chain to glycolipid-enriched membrane domains upon T cell activation.
A. Kosugi, S.-i. Saitoh, S. Noda, K. Yasuda, F. Hayashi, M. Ogata, and T. Hamaoka (1999)
Int. Immunol. 11, 1395-1401
   Abstract »    Full Text »    PDF »
Signals Transduced by CD3{epsilon}, But Not by Surface Pre-TCR Complexes, Are Able to Induce Maturation of an Early Thymic Lymphoma In Vitro.
M. Carleton, N. R. Ruetsch, M. A. Berger, M. Rhodes, S. Kaptik, and D. L. Wiest (1999)
J. Immunol. 163, 2576-2585
   Abstract »    Full Text »    PDF »
Phospho-LAT-Independent Activation of the Ras-Mitogen-Activated Protein Kinase Pathway: A Differential Recruitment Model of TCR Partial Agonist Signaling.
L. A. Chau and J. Madrenas (1999)
J. Immunol. 163, 1853-1858
   Abstract »    Full Text »    PDF »
Differential CD3{zeta} Phosphorylation Is Not Required for the Induction of T Cell Antagonism by Altered Peptide Ligands.
H. Liu and D. A. A. Vignali (1999)
J. Immunol. 163, 599-602
   Abstract »    Full Text »    PDF »
The Immunological Synapse: A Molecular Machine Controlling T Cell Activation.
A. Grakoui, S. K. Bromley, C. Sumen, M. M. Davis, A. S. Shaw, P. M. Allen, and M. L. Dustin (1999)
Science 285, 221-227
   Abstract »    Full Text »
Anergic CD8+ T Cells Can Persist and Function In Vivo.
C. A. Blish, S. R. Dillon, A. G. Farr, and P. J. Fink (1999)
J. Immunol. 163, 155-164
   Abstract »    Full Text »    PDF »
A Kinetic Threshold between Negative and Positive Selection Based on the Longevity of the T Cell Receptor-Ligand Complex.
C. B. Williams, D. L. Engle, G. J. Kersh, J. Michael White, and P. M. Allen (1999)
J. Exp. Med. 189, 1531-1544
   Abstract »    Full Text »    PDF »
Microbial Epitopes Act as Altered Peptide Ligands to Prevent Experimental Autoimmune Encephalomyelitis.
P. J. Ruiz, H. Garren, D. L. Hirschberg, A. M. Langer-Gould, M. Levite, M. V. Karpuj, S. Southwood, A. Sette, P. Conlon, and L. Steinman (1999)
J. Exp. Med. 189, 1275-1284
   Abstract »    Full Text »    PDF »
Caspase-mediated Degradation of T-Cell Receptor {{zeta}}-Chain.
B. R. Gastman, D. E. Johnson, T. L. Whiteside, and H. Rabinowich (1999)
Cancer Res. 59, 1422-1427
   Abstract »    Full Text »    PDF »
Cutting Edge: A Test of the Dominant Negative Signal Model for TCR Antagonism.
M. A. Daniels, S. L. Schober, K. A. Hogquist, and S. C. Jameson (1999)
J. Immunol. 162, 3761-3764
   Abstract »    Full Text »    PDF »
Definition of the Sites of Interaction between the Protein Tyrosine Phosphatase SHP-1 and CD22.
J. Blasioli, S. Paust, and M. L. Thomas (1999)
J. Biol. Chem. 274, 2303-2307
   Abstract »    Full Text »    PDF »
The Second Domain of the CD45 Protein Tyrosine Phosphatase Is Critical for Interleukin-2 Secretion and Substrate Recruitment of TCR-zeta in Vivo.
N. Kashio, W. Matsumoto, S. Parker, and D. M. Rothstein (1998)
J. Biol. Chem. 273, 33856-33863
   Abstract »    Full Text »    PDF »
T cell receptor antagonism in vivo, at last.
S. C. Jameson (1998)
PNAS 95, 14001-14002
   Full Text »    PDF »
Signaling in human lupus T lymphocytes.
M. Zouali (1998)
Lupus 7, 499-502
   PDF »
T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4.
Y. Xiong, P. Kern, H.-C. Chang, and E. L. Reinherz (2001)
J. Biol. Chem. 276, 5659-5667
   Abstract »    Full Text »    PDF »
The Human CD8 Coreceptor Effects Cytotoxic T Cell Activation and Antigen Sensitivity Primarily by Mediating Complete Phosphorylation of the T Cell Receptor zeta Chain.
M. A. Purbhoo, J. M. Boulter, D. A. Price, A.-L. Vuidepot, C. S. Hourigan, P. R. Dunbar, K. Olson, S. J. Dawson, R. E. Phillips, B. K. Jakobsen, et al. (2001)
J. Biol. Chem. 276, 32786-32792
   Abstract »    Full Text »    PDF »
The T Cell Receptor for Antigen: Signaling and Ligand Discrimination.
R. N. Germain (2001)
J. Biol. Chem. 276, 35223-35226
   Full Text »    PDF »
Fully competent dendritic cells as inducers of T cell anergy in autoimmunity.
S. Quaratino, L. P. Duddy, and M. Londei (2000)
PNAS 97, 10911-10916
   Abstract »    Full Text »    PDF »



To Advertise     Find Products


Science. ISSN 0036-8075 (print), 1095-9203 (online)