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

J Leukoc Biol. 2007 Jan;81(1):319-27. doi: 10.1189/jlb.0606378. Epub 2006 Oct 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / pharmacology
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / physiology
  • Antimetabolites / pharmacology
  • Calcineurin / metabolism*
  • Cells, Cultured
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Isoxazoles / pharmacology
  • Models, Immunological
  • NF-kappa B / metabolism*
  • Nitriles / pharmacology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / physiology


  • Alkynes
  • Antimetabolites
  • Immunosuppressive Agents
  • Isoxazoles
  • NF-kappa B
  • Nitriles
  • 2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide
  • Calcineurin