The effect of the immunosuppressant FK-506 on alternate pathways of T cell activation

Eur J Immunol. 1991 Feb;21(2):439-45. doi: 10.1002/eji.1830210228.

Abstract

Structurally unrelated, FK-506 and cyclosporin (CsA) bind to and inhibit the action of distinct cytoplasmic receptors, FK-506-binding protein (FKBP) and cyclophilin (CyP), respectively. These receptors, termed immunophilins, share no sequence similarity, and yet both have been demonstrated to be capable of catalyzing the cis-trans isomerization of peptidyl-prolyl bonds (rotamase activity). Because FK-506 and CsA bind to different intracellular target structures, we investigated the spectrum of action of FK-506, in comparison to CsA, on T cell activation. We have shown that FK-506, like CsA, is able to inhibit T cell activation mediated not only by the T cell receptor-CD3 complex, but also via another surface molecule, CD2. T cell proliferation, stimulation of interleukin 2 production, and induction of apoptosis were all sensitive to inhibition by both FK-506 and CsA. With each parameter of activation, FK-506 is approximately 10-100-fold more effective than CsA. In contrast, FK-506 did not affect T cell proliferation induced by anti-CD28 monoclonal antibody in the presence of phorbol 12-myristate 13-acetate. This CD28 pathway, however, was inhibited by a structural homology of FK-506, rapamycin, demonstrating that the mechanism of action of FK-506 has specificity. These data suggest that immunophilins or the complex of drug coupled to immunophilin (i.e. FK-506/FKBP, CsA/CyP) are involved in and regulate selective pathways of T cell stimulation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antigens, CD / physiology
  • Antigens, Differentiation, T-Lymphocyte / physiology
  • CD2 Antigens
  • CD28 Antigens
  • CD3 Complex
  • Cell Survival / drug effects
  • Cyclosporins / pharmacology
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Lymphocyte Activation / drug effects*
  • Mice
  • Polyenes / pharmacology
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Immunologic / physiology
  • Sirolimus
  • T-Lymphocytes / drug effects*
  • Tacrolimus

Substances

  • Anti-Bacterial Agents
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD2 Antigens
  • CD28 Antigens
  • CD3 Complex
  • Cyclosporins
  • Immunosuppressive Agents
  • Polyenes
  • Receptors, Antigen, T-Cell
  • Receptors, Immunologic
  • Sirolimus
  • Tacrolimus