A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a concentration-dependent switch from costimulation to inhibition

Hiroki Kawano, Yoshio Katayama, Kentaro Minagawa, Manabu Shimoyama, Mark Henkemeyer, Toshimitsu Matsui

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1562-1572
Number of pages11
JournalEuropean Journal of Immunology
Volume42
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

Ephrin-B1
Ephrin-B2
Ephrins
Ephrin-B3
T-Lymphocytes
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Phosphorylation
Cell Proliferation
Eph Family Receptors
Cell Communication
Axons
Ligands

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Kawano, Hiroki ; Katayama, Yoshio ; Minagawa, Kentaro ; Shimoyama, Manabu ; Henkemeyer, Mark ; Matsui, Toshimitsu. / A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a concentration-dependent switch from costimulation to inhibition. In: European Journal of Immunology. 2012 ; Vol. 42, No. 6. pp. 1562-1572.
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A novel feedback mechanism by Ephrin-B1/B2 in T-cell activation involves a concentration-dependent switch from costimulation to inhibition. / Kawano, Hiroki; Katayama, Yoshio; Minagawa, Kentaro; Shimoyama, Manabu; Henkemeyer, Mark; Matsui, Toshimitsu.

In: European Journal of Immunology, Vol. 42, No. 6, 01.06.2012, p. 1562-1572.

Research output: Contribution to journalArticle

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AU - Kawano, Hiroki

AU - Katayama, Yoshio

AU - Minagawa, Kentaro

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AU - Henkemeyer, Mark

AU - Matsui, Toshimitsu

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