The effect of the immunosuppressant FK-506 on alternate pathways of T cell activation.
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.
Bierer
B E
BE
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Schreiber
S L
SL
Burakoff
S J
SJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D011090:Polyenes / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus
D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D011090:Polyenes; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D020123:Sirolimus; D016559:Tacrolimus