Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin

J Immunol. 1990 Jan 1;144(1):251-8.


FK-506 and the structurally related macrolide rapamycin (RAP) were investigated in comparison with cyclosporin A (CsA) for their immunosuppressive effects on murine T cells. All three agents suppressed the proliferation of splenic T cells triggered by lectins or antibodies to CD3 and Ly-6C. FK-506 or CsA also inhibited proliferation, IL-2 production, and IL-2R expression in splenic T cells activated with ionomycin + PMA. However, RAP minimally affected IL-2 production and IL-2R expression in these cells, although it reduced proliferation. Similarly, FK-506 and CsA, but not RAP, suppressed IL-2 production by activated DO.11.10 T hybridoma cells. In such a system, as well as in normal T cells stimulated with high ionomycin concentrations, FK-506 and CsA enhanced proliferation, indicating that they both abrogate negative signals associated with T cell activation. On the contrary, RAP diminished the autonomous proliferation of hybridoma cells, whereas FK-506 and CsA had little effect. The proliferative response induced in D10.G4 cells by IL-1 + ionomycin but not that induced by IL-1 + PMA was sensitive to inhibition by FK-506 and CsA. In contrast, RAP inhibited equally well both types of stimulation. Finally, T cell proliferation driven by IL-2 or IL-4 was found to be relatively resistant to FK-506 or CsA but sensitive to RAP. Altogether, these data demonstrate that FK-506 and CsA alter similar calcium-associated events of T cell activation and block T cell proliferation primarily by suppressing lymphokine production. RAP interferes with a different set of events and inhibits T cells by impairing their response to growth-promoting lymphokines.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Cyclosporins / pharmacology
  • Hybridomas
  • Immunosuppressive Agents / pharmacology*
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / biosynthesis
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / biosynthesis
  • Ionomycin / pharmacology
  • Lymphocyte Activation / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Polyenes / pharmacology
  • Receptors, Interleukin-2 / metabolism
  • Sirolimus
  • Tacrolimus
  • Tetradecanoylphorbol Acetate / pharmacology


  • Anti-Bacterial Agents
  • Cyclosporins
  • Immunosuppressive Agents
  • Interleukin-2
  • Polyenes
  • Receptors, Interleukin-2
  • Interleukin-4
  • Ionomycin
  • Tetradecanoylphorbol Acetate
  • Sirolimus
  • Tacrolimus