Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway.
The consequences of T-cell activation depend exclusively on costimulation during antigen-T-cell receptor interaction. Interaction between the T-cell coreceptor CD28 and its ligand B7 during antigen-antigen receptor engagement results in full activation of T cells, the outcomes of which are proliferation and effector functions. The ability of CD28 to costimulate the production of interleukin-2 (IL-2) explains the importance of this costimulation. The signaling event mediated by CD28 engagement has been proposed to have 2 components: one is sensitive to the immunosuppressive drug cyclosporin A (CsA), and the other one is CsA-resistant. In this report, we demonstrate that the CsA-resistant pathway is sensitive to the immunosuppressive drug rapamycin. Treatment with rapamycin blocked IL-2 production after activation of human peripheral blood T cells with phorbol ester (PMA) and anti-CD28 (CsA-resistant pathway), whereas this drug did not have any effect on PMA plus ionomycin stimulation (CsA-sensitive pathway). The inhibitory effect of rapamycin was on messenger RNA stability and translation, rather than on IL-2 transcription or protein turnover.
Ghosh
Paritosh
P
Lymphocyte Cell Biology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. ghoshp@grc.nia.nih.gov
Buchholz
Meredith A
MA
Yano
Shingo
S
Taub
Dennis
D
Longo
Dan L
DL
D018106:CD28 Antigens / Q000502:physiology*; D016572:Cyclosporine; D004351:Drug Resistance; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016572:Cyclosporine; D020123:Sirolimus