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

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© 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

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, Yasushi Saito^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

Correspondence to: Takashi Saito, Dept. of Molecular Genetics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel:81-43-226-2198 Fax:81-43-222-1791 E-mail: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

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