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Science 3 October 1997:
Vol. 278. no. 5335, pp. 124 - 128
DOI: 10.1126/science.278.5335.124
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Reports

Maintenance of Human T Cell Anergy: Blocking of IL-2 Gene Transcription by Activated Rap1

Vassiliki A. Boussiotis, * Gordon J. Freeman, Alla Berezovskaya, Dwayne L. Barber, Lee M. Nadler

In the absence of costimulation, T cells activated through their antigen receptor become unresponsive (anergic) and do not transcribe the gene encoding interleukin-2 (IL-2) when restimulated with antigen. Anergic alloantigen-specific human T cells contained phosphorylated Cbl that coimmunoprecipitated with Fyn. The adapter protein CrkL was associated with both phosphorylated Cbl and the guanidine nucleotide-releasing factor C3G, which catalyzes guanosine triphosphate (GTP) exchange on Rap1. Active Rap1 (GTP-bound form) was present in anergic cells. Forced expression of low amounts of Rap1-GTP in Jurkat T cells recapitulated the anergic defect and blocked T cell antigen receptor (TCR)- and CD28-mediated IL-2 gene transcription. Therefore, Rap1 functions as a negative regulator of TCR-mediated IL-2 gene transcription and may be responsible for the specific defect in IL-2 production in T cell anergy.

V. A. Boussiotis, G. J. Freeman, A. Berezovskaya, L. M. Nadler, Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
D. L. Barber, Division of Cellular and Molecular Biology, Ontario Cancer Institute, Toronto, Ontario, M5G 2M9, Canada.
*   To whom correspondence should be addressed. E-mail: vassiliki_boussiotis{at}macmailgw.dfci.harvard.edu

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   Abstract »    Full Text »    PDF »
Impaired Ca/calcineurin pathway in in vivo anergized CD4 T cells.
M. Kimura, M. Yamashita, M. Kubo, M. Iwashima, C. Shimizu, K. Tokoyoda, J. Chiba, M. Taniguchi, M. Katsumata, and T. Nakayama (2000)
Int. Immunol. 12, 817-824
   Abstract »    Full Text »    PDF »
Cloning and Characterization of Human Lnk, an Adaptor Protein with Pleckstrin Homology and Src Homology 2 Domains that Can Inhibit T Cell Activation.
Y. Li, X. He, J. Schembri-King, S. Jakes, and J. Hayashi (2000)
J. Immunol. 164, 5199-5206
   Abstract »    Full Text »    PDF »
Signaling of Hepatocyte Growth Factor/Scatter Factor (HGF) to the Small GTPase Rap1 via the Large Docking Protein Gab1 and the Adapter Protein CRKL.
D. Sakkab, M. Lewitzky, G. Posern, U. Schaeper, M. Sachs, W. Birchmeier, and S. M. Feller (2000)
J. Biol. Chem. 275, 10772-10778
   Abstract »    Full Text »    PDF »
Effects of Cigarette Smoke on Immune Response: Chronic Exposure to Cigarette Smoke Impairs Antigen-Mediated Signaling in T Cells and Depletes IP3-Sensitive Ca2+ Stores.
R. Kalra, S. P. Singh, S. M. Savage, G. L. Finch, and M. L. Sopori (2000)
J. Pharmacol. Exp. Ther. 293, 166-171
   Abstract »    Full Text »
Rap1 Is a Potent Activation Signal for Leukocyte Function-Associated Antigen 1 Distinct from Protein Kinase C and Phosphatidylinositol-3-OH Kinase.
K. Katagiri, M. Hattori, N. Minato, S.-k. Irie, K. Takatsu, and T. Kinashi (2000)
Mol. Cell. Biol. 20, 1956-1969
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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 »
Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction.
K. A. Frauwirth, M.-L. Alegre, and C. B. Thompson (2000)
J. Immunol. 164, 2987-2993
   Abstract »    Full Text »    PDF »
Divergent Roles for Ras and Rap in the Activation of p38 Mitogen-activated Protein Kinase by Interleukin-1.
E. M. Palsson, M. Popoff, M. Thelestam, and L. A. J. O'Neill (2000)
J. Biol. Chem. 275, 7818-7825
   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 »
Cbl Suppresses B Cell Receptor-mediated Phospholipase C (PLC)-{gamma}2 Activation by Regulating B Cell Linker Protein-PLC-{gamma}2 Binding.
T. Yasuda, A. Maeda, M. Kurosaki, T. Tezuka, K. Hironaka, T. Yamamoto, and T. Kurosaki (2000)
J. Exp. Med. 191, 641-650
   Abstract »    Full Text »    PDF »
IFN-{gamma} Activates the C3G/Rap1 Signaling Pathway.
Y. Alsayed, S. Uddin, S. Ahmad, B. Majchrzak, B. J. Druker, E. N. Fish, and L. C. Platanias (2000)
J. Immunol. 164, 1800-1806
   Abstract »    Full Text »    PDF »
c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology.
R. Scaife and W. Langdon (2000)
J. Cell Sci. 113, 215-226
   Abstract »    PDF »
The Inhibitory Function of CTLA-4 Does Not Require Its Tyrosine Phosphorylation.
M. L. Baroja, D. Luxenberg, T. Chau, V. Ling, C. A. Strathdee, B. M. Carreno, and J. Madrenas (2000)
J. Immunol. 164, 49-55
   Abstract »    Full Text »    PDF »
Anergic T Lymphocytes Selectively Express an Integrin Regulatory Protein of the Cytohesin Family.
U. Korthauer, W. Nagel, E. M. Davis, M. M. Le Beau, R. S. Menon, E. O. Mitchell, C. A. Kozak, W. Kolanus, and J. A. Bluestone (2000)
J. Immunol. 164, 308-318
   Abstract »    Full Text »    PDF »
The Adapter Protein Crkl Links Cbl to C3G after Integrin Ligation and Enhances Cell Migration.
N. Uemura and J. D. Griffin (1999)
J. Biol. Chem. 274, 37525-37532
   Abstract »    Full Text »    PDF »
PDZ-GEF1, a Guanine Nucleotide Exchange Factor Specific for Rap1 and Rap2.
J. de Rooij, N. M. Boenink, M. van Triest, R. H. Cool, A. Wittinghofer, and J. L. Bos (1999)
J. Biol. Chem. 274, 38125-38130
   Abstract »    Full Text »    PDF »
Negative Regulation of CD4 Lineage Development and Responses by CD5.
C. Pena-Rossi, L. A. Zuckerman, J. Strong, J. Kwan, W. Ferris, S. Chan, A. Tarakhovsky, A. D. Beyers, and N. Killeen (1999)
J. Immunol. 163, 6494-6501
   Abstract »    Full Text »    PDF »
Antigen-Experienced T Cells Undergo a Transient Phase of Unresponsiveness Following Optimal Stimulation.
F. De Mattia, S. Chomez, F. Van Laethem, V. Moulin, J. Urbain, M. Moser, O. Leo, and F. Andris (1999)
J. Immunol. 163, 5929-5936
   Abstract »    Full Text »    PDF »
Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients.
P. Romagnoli and C. Bron (1999)
Int. Immunol. 11, 1411-1422
   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 »


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