title: A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a concentration-dependent switch from costimulation to inhibition.
abstract: Bidirectional signals via Eph receptors/ephrins have been recognized as major forms of contact-dependent cell communications such as cell attraction and repulsion. T cells express EphBs, and their ligands, the ephrin-Bs, have been known as costimulatory molecules for T-cell proliferation. Recently, another remarkable feature of ephrin-As has emerged in the form of a concentration-dependent transition from promotion to inhibition in axon growth. Here we examined whether this modification plays a role in ephrin-B costimulation in murine primary T cells. Low doses of ephrin-B1 and ephrin-B2 costimulated T-cell proliferation induced by anti-CD3, but high concentrations strongly inhibited it. In contrast, ephrin-B3 showed a steadily increasing stimulatory effect. This modulation was virtually preserved in T cells from mice simultaneously lacking four genes, EphB1, EphB2, EphB3, and EphB6. High concentrations of ephrin-B1/B2, but not ephrin-B3, inhibited the anti-CD3-induced phosphorylation of Lck and its downstream signals such as Erk and Akt. Additionally, high doses of any ephrin-Bs could phosphorylate EphB4. However, only ephrin-B1/B2 but not ephrin-B3 recruited SHP1, a phosphatase to suppress the phosphorylation of Lck. These data suggest that EphB4 signaling could engage in negative feedback to TCR signals. T-cell activation may be finely adjusted by the combination and concentration of ephrin-Bs expressed in the immunological microenvironment.
authors.affiliation: Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawano
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Katayama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Minagawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Shimoyama
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Matsui
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D036387:Ephrin-B1 / Q000494:pharmacology*; D036388:Ephrin-B2 / Q000494:pharmacology*; D025461:Feedback, Physiological; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology; D036223:Receptor, EphB3 / Q000494:pharmacology; D036224:Receptor, EphB4 / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D036387:Ephrin-B1; D036388:Ephrin-B2; D011948:Receptors, Antigen, T-Cell; C086681:Ephb4 protein, mouse; D036223:Receptor, EphB3; D036224:Receptor, EphB4; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6