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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

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 Nakasekoa,d, Shoichiro Miyatakeb, Tomohiko Iidaa, Satoru Haraa,d, Ryo Abec, Hiroshi Ohnoa,d, and Takashi Saitoa

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 costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif (165YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain–containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for 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 tyrosine phosphatase; WT, wild-type

H. Ohno's present address is the Division of Molecular Membrane Biology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.

© 1999 The Rockefeller University Press


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