Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Engagement Delivers an Inhibitory Signal through the Membrane-Proximal Region in the Absence of the Tyrosine Motif in the Cytoplasmic Tail

doi:10.1084/jem.190.6.765

This Article

	Full Text
	Full Text (PDF, 204K)
	PPT slides of all figures
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Nakaseko, C.
	Articles by Saito, T.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Nakaseko, C.
	Articles by Saito, T.


Social Bookmarking

	What's this?

© The Rockefeller University Press, 0022-1007/1999/9/765/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 6, September 20, 1999 765-774

Original Article

Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Engagement Delivers an Inhibitory Signal through the Membrane-Proximal Region in the Absence of the Tyrosine Motif in the Cytoplasmic Tail

Chiaki Nakaseko^a^,d, Shoichiro Miyatake^b, Tomohiko Iida^a, Satoru Hara^a^,d, Ryo Abe^c, Hiroshi Ohno^a^,d, and Takashi Saito^a

^a Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
^b Department of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
^c Division of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba 278-8510, Japan
^d Second Department of Internal Medicine, Chiba University School of Medicine, Chiba 260-8670, Japan
Dept. of Molecular Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.81-43-222-179181-43-226-2198

saito{at}med.m.chiba-u.ac.jp

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulationreceptor that delivers inhibitory signals upon activation. Althoughthe tyrosine-based motif (¹⁶⁵YVKM) within its cytoplasmic tailhas been shown to associate in vitro with Src homology 2 domain–containingtyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinaseupon phosphorylation, the mechanism of negative signaling remainsunclear. Here, we report a new mechanism of negative signalingbased on the analysis of murine T cell clones transfected withvarious mutants of CTLA-4. Upon T cell activation by cross-linkingwith anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibitedboth proliferation and interleukin 2 production in tyrosinemutants as well as in wild-type CTLA-4 transfectants. Furthermore,the mutant CTLA-4 lacking most of the cytoplasmic region stronglysuppressed interleukin 2 production as well. These data suggestthat negative signals by CTLA-4 could be mediated through themembrane-proximal region of CTLA-4 but not through the YVKMmotif and that the association of CTLA-4 with SHP-2 is not requiredfor CTLA-4–mediated suppression of T cell activation.

Key Words: CTLA-4 • costimulation • negative signal • tyrosine motif

1used in this paper: AP-2, adaptor protein complex 2; CTLA-4,CTL antigen 4; ERK2, extracellular signal-regulated kinase 2;MAPK, mitogen-activated protein kinase; MBP, myelin basic protein;PI3, phosphatidylinositol 3; RT, reverse transcriptase; SH2,Src homology 2; SHP-2, SH2 domain–containing tyrosinephosphatase; WT, wild-type

H. Ohno's present address is the Division of Molecular MembraneBiology, Cancer Research Institute, Kanazawa University, Kanazawa920-0934, Japan.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Berg, M., Zavazava, N. (2008). Regulation of CD28 expression on CD8+ T cells by CTLA-4. J. Leukoc. Biol. 83: 853-863 [Abstract] [Full Text]
Chemnitz, J. M., Lanfranco, A. R., Braunstein, I., Riley, J. L. (2006). B and T Lymphocyte Attenuator-Mediated Signal Transduction Provides a Potent Inhibitory Signal to Primary Human CD4 T Cells That Can Be Initiated by Multiple Phosphotyrosine Motifs.. J. Immunol. 176: 6603-6614 [Abstract] [Full Text]
Salmond, R. J., Huyer, G., Kotsoni, A., Clements, L., Alexander, D. R. (2005). The src Homology 2 Domain-Containing Tyrosine Phosphatase 2 Regulates Primary T-Dependent Immune Responses and Th Cell Differentiation. J. Immunol. 175: 6498-6508 [Abstract] [Full Text]
Dillon, T. J., Carey, K. D., Wetzel, S. A., Parker, D. C., Stork, P. J. S. (2005). Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4. Mol. Cell. Biol. 25: 4117-4128 [Abstract] [Full Text]
Kataoka, H., Takahashi, S., Takase, K., Yamasaki, S., Yokosuka, T., Koike, T., Saito, T. (2005). CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4. Int Immunol 17: 421-427 [Abstract] [Full Text]
Madrenas, J., Chau, L. A., Teft, W. A., Wu, P. W., Jussif, J., Kasaian, M., Carreno, B. M., Ling, V. (2004). Conversion of CTLA-4 from Inhibitor to Activator of T Cells with a Bispecific Tandem Single-Chain Fv Ligand. J. Immunol. 172: 5948-5956 [Abstract] [Full Text]
Yi, L. A., Hajialiasgar, S., Chuang, E. (2004). Tyrosine-mediated inhibitory signals contribute to CTLA-4 function in vivo. Int Immunol 16: 539-547 [Abstract] [Full Text]
Hirashima, M, Fukazawa, T, Abe, K, Morita, Y, Kusaoi, M, Hashimoto, H (2004). Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients. Lupus 13: 24-31 [Abstract]
Chwae, Y.-J., Chang, M. J., Park, S. M., Yoon, H., Park, H.-J., Kim, S. J., Kim, J. (2002). Molecular Mechanism of the Activation-Induced Cell Death Inhibition Mediated by a p70 Inhibitory Killer Cell Ig-Like Receptor in Jurkat T Cells. J. Immunol. 169: 3726-3735 [Abstract] [Full Text]
Chambers, C. A., Kang, J., Wu, Y., Held, W., Raulet, D. H., Allison, J. P. (2002). The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor. Blood 99: 4509-4516 [Abstract] [Full Text]
Darlington, P. J., Baroja, M. L., Chau, T. A., Siu, E., Ling, V., Carreno, B. M., Madrenas, J. (2002). Surface Cytotoxic T Lymphocyte-associated Antigen 4 Partitions Within Lipid Rafts and Relocates to the Immunological Synapse under Conditions of Inhibition of T Cell Activation. JEM 195: 1337-1347 [Abstract] [Full Text]
Baroja, M. L., Vijayakrishnan, L., Bettelli, E., Darlington, P. J., Chau, T. A., Ling, V., Collins, M., Carreno, B. M., Madrenas, J., Kuchroo, V. K. (2002). Inhibition of CTLA-4 Function by the Regulatory Subunit of Serine/Threonine Phosphatase 2A. J. Immunol. 168: 5070-5078 [Abstract] [Full Text]
Bai, X.-F., Liu, J., May, K. F. Jr, Guo, Y., Zheng, P., Liu, Y. (2002). B7-CTLA4 interaction promotes cognate destruction of tumor cells by cytotoxic T lymphocytes in vivo. Blood 99: 2880-2889 [Abstract] [Full Text]
Mirshahidi, S., Huang, C.-T., Sadegh-Nasseri, S. (2001). Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor. JEM 194: 719-732 [Abstract] [Full Text]
Latour, S., Tanaka, H., Demeure, C., Mateo, V., Rubio, M., Brown, E. J., Maliszewski, C., Lindberg, F. P., Oldenborg, A., Ullrich, A., Delespesse, G., Sarfati, M. (2001). Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation. J. Immunol. 167: 2547-2554 [Abstract] [Full Text]
Burr, J. S., Kimzey, S. L., Randolph, D. R., Green, J. M. (2001). CD28 and CTLA4 Coordinately Regulate Airway Inflammatory Cell Recruitment and T-Helper Cell Differentiation after Inhaled Allergen. Am. J. Respir. Cell Mol. Bio. 24: 563-568 [Abstract] [Full Text]
Newman, D. K., Hamilton, C., Newman, P. J. (2001). Inhibition of antigen-receptor signaling by Platelet Endothelial Cell Adhesion Molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56lck. Blood 97: 2351-2357 [Abstract] [Full Text]
Iida, T., Ohno, H., Nakaseko, C., Sakuma, M., Takeda-Ezaki, M., Arase, H., Kominami, E., Fujisawa, T., Saito, T. (2000). Regulation of Cell Surface Expression of CTLA-4 by Secretion of CTLA-4-Containing Lysosomes Upon Activation of CD4+ T Cells. J. Immunol. 165: 5062-5068 [Abstract] [Full Text]
Carreno, B. M., Bennett, F., Chau, T. A., Ling, V., Luxenberg, D., Jussif, J., Baroja, M. L., Madrenas, J. (2000). CTLA-4 (CD152) Can Inhibit T Cell Activation by Two Different Mechanisms Depending on Its Level of Cell Surface Expression. J. Immunol. 165: 1352-1356 [Abstract] [Full Text]
Ikushima, H., Munakata, Y., Ishii, T., Iwata, S., Terashima, M., Tanaka, H., Schlossman, S. F., Morimoto, C. (2000). Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc. Natl. Acad. Sci. USA 97: 8439-8444 [Abstract] [Full Text]
Green, J. M. (2000). The B7/CD28/CTLA4 T-Cell Activation Pathway . Implications for Inflammatory Lung Disease. Am. J. Respir. Cell Mol. Bio. 22: 261-264 [Full Text]
Baroja, M. L., Luxenberg, D., Chau, T., Ling, V., Strathdee, C. A., Carreno, B. M., Madrenas, J. (2000). The Inhibitory Function of CTLA-4 Does Not Require Its Tyrosine Phosphorylation. J. Immunol. 164: 49-55 [Abstract] [Full Text]
Yamasaki, S., Nishida, K., Hibi, M., Sakuma, M., Shiina, R., Takeuchi, A., Ohnishi, H., Hirano, T., Saito, T. (2001). Docking Protein Gab2 Is Phosphorylated by ZAP-70 and Negatively Regulates T Cell Receptor Signaling by Recruitment of Inhibitory Molecules. J. Biol. Chem. 276: 45175-45183 [Abstract] [Full Text]