In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 81, No. 1 ( 2007-01-01), p. 319-327
Abstract:
A stable supramolecular cluster in T cells at the contact site of APCs, the immunological synapse (IS), is essential for full T cell activation. Failure of IS maturation, as determined by defective relocalization of the TCR/CD3 complex at the T cell/APC contact site, is linked with T cell hyporesponsiveness. The effects of clinically used immunosuppressants on these critical events, however, are undefined. Here, we show that treatment of T cells with cyclosporin A, FK506, and dexamethasone, which are known to inhibit calcineurin and NF-κB, respectively, but not rapamycin, the inhibitor of mammalian target of rapamycin, selectively prevented TCR/CD3 relocalization into the IS, while relocalization of adhesion and cytoskeletal proteins as well as T cell/APC conjugate formation remained unaltered. The involvement of calcineurin and NF-κB in IS maturation was confirmed by using specific inhibitors of these molecules (FR901725, gossypol, SN50). FK778, as an inhibitor of DNA replication and also TCR/CD3-activated tyrosine kinases, globally abrogated cytoskeletal, adhesion, and signaling molecule relocalization, thereby preventing formation of an IS at an earlier, immature stage along with impaired, antigen-specific T cell/APC conjugate formation. Collectively, blocking IS formation at distinct stages may mediate effects on T cell activation of currently used immunosuppressants, apart from their capacity to block gene transcription, cytokine signaling, and DNA replication. Furthermore, these data imply novel functions of calcineurin and NF-κB for successful IS maturation.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2007
detail.hit.zdb_id:
2026833-6
SSG:
12
Bookmarklink
