Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 6, Pages 1562-1572Publisher
WILEY
DOI: 10.1002/eji.201142175
Keywords
Biphasic modulation center dot EphB center dot Ephrin-B center dot TCR
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Funding
- Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT) [20012033]
- Japan Society for the Promotion of Science (JSPS) [21591243]
- Ministry of Health, Welfare, and Labor in Japan [H22-GANNRINSHO-Ippan032]
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [20012033, 21591243, 22591037] Funding Source: KAKEN
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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.
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