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Published online before print October 12, 2006

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(Journal of Leukocyte Biology. 2007;81:319-327.)
© 2007 by Society for Leukocyte Biology

Impairment of T cell interactions with antigen-presenting cells by immunosuppressive drugs reveals involvement of calcineurin and NF-B in immunological synapse formation

Maximilian Zeyda^*, René Geyeregger^*, Marko Poglitsch, Thomas Weichhart, Gerhard J. Zlabinger, Shigeo Koyasu, Walter H. Hörl, Thomas M. Stulnig^*, Bruno Watschinger and Marcus D. Saemann^,1

Department of Internal Medicine III,
^* Clinical Divisions of Endocrinology and Metabolism and
Nephrology and Dialysis, and
Institute of Immunology, Medical University of Vienna, Vienna, Austria; and
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

¹Correspondence: Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: marcus.saemann{at}meduniwien.ac.at

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-B, 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-B 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-B for successful IS maturation.

Key Words: supramolecular activation clusters • human T cell activation • immunosuppression