title: Novel CD3-specific antibody induces immunosuppression via impaired phosphorylation of LAT and PLCγ1 following T-cell stimulation.
abstract: The activation of T cells is known to be accompanied by the temporary downmodulation of the TCR/CD3 complex on the cell surface. Here, we established a novel monoclonal antibody, Dow2, that temporarily induces downmodulation of the TCR/CD3 complex in mouse CD4(+) T cells without activating T cells. Dow2 recognized the determinant on CD3ε; however, differences were observed in the binding mode between Dow2 and the agonistic anti-CD3ε Ab, 145-2C11. An injection of Dow2 in vivo resulted in T-cell anergy, and prolonged the survival of cardiac allografts without a marked increase in cytokine release. The phosphorylated forms of the signaling proteins PLC-γ1 and LAT in Dow2-induced anergic T cells were markedly decreased upon stimulation. However, the levels of phosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells could be rescued in the presence of the proteasome inhibitor MG-132. These results suggest that proteasome-mediated degradation is involved in hypophosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells. The novel CD3-specific Ab, Dow2, may provide us with a unique tool for inducing immunosuppression.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shiheido
authors.forename: Takane
authors.initials: T
authors.lastname: Aoyama
authors.forename: Honami
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kaori
authors.initials: K
authors.lastname: Hanaoka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Abe
authors.forename: Emi
authors.initials: E
authors.lastname: Nishida
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Orie
authors.initials: O
authors.lastname: Koga
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Shibagaki
authors.forename: Akimichi
authors.initials: A
authors.lastname: Morita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nikawa
authors.forename: Seisuke
authors.initials: S
authors.lastname: Hattori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D017635:Clonal Anergy / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051966:Phospholipase C gamma / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D059748:Proteolysis / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058846:Antibodies, Monoclonal, Murine-Derived; D017252:CD3 Complex; C485468:Cd3e protein, mouse; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Anergy; Antibody; LAT; PLCγ1