Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-kappaB in immunological synapse formation.
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-kappaB, 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-kappaB 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-kappaB for successful IS maturation.
Zeyda
Maximilian
M
Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Geyeregger
René
R
Poglitsch
Marko
M
Weichhart
Thomas
T
Zlabinger
Gerhard J
GJ
Koyasu
Shigeo
S
Hörl
Walter H
WH
Stulnig
Thomas M
TM
Watschinger
Bruno
B
Saemann
Marcus D
MD
D000480:Alkynes / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000502:physiology; D000963:Antimetabolites / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology
D000480:Alkynes; D000963:Antimetabolites; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016328:NF-kappa B; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D019703:Calcineurin