Inhibition of re-expression of surface CD4, but not CD8, on activated human T-lymphocytes by the immunosuppressive drugs dexamethasone and cyclosporine A: correlation with inhibition of proliferation.
Our objective was to study the re-expression of CD4 and CD8 on activated human T-lymphocytes in the presence of dexamethasone and cyclosporine A at physiologically relevant concentrations. Peripheral blood mononuclear cells from 12 healthy volunteers were cultured for up to 72 h in the presence and absence of phytohaemagglutinin A (PHA) and dexamethasone and cyclosporine A at a range of concentrations. Expression of surface CD3, CD4 and CD8 and the activation marker CD25 was quantified on T-lymphocytes using flow cytometry. T-lymphocytes cultured with PHA showed significant (P < 0.01) reduction in the expression of surface CD3, CD4 and CD8 compared with cells cultured in medium alone, which was apparent as early as 0.5 h after PHA exposure. The reduction in the expression of both CD4 and CD8 in the first 0.5 h after exposure correlated with that of CD3 (P < 0.02). Expression of CD4 and CD8 subsequently increased again, so that by 48 h after exposure CD4 expression was no longer significantly different to that of cells cultured in medium alone. CD8 expression recovered later, but within 72 h. Both dexamethasone and cyclosporine A, when added at the commencement of the cultures, significantly inhibited, in a concentrated-dependent (10(-6)-10(-9) mol/l) fashion, the re-expression of CD4, but not CD8, on the PHA-stimulated T-lymphocytes measured after 48 h. In contrast, CD25 expression on both CD4 and CD8 T-lymphocytes was inhibited by both drugs to an equivalent extent over the same range of concentrations. At this time point, the degree of inhibition of CD4 re-expression by both drugs correlated significantly with the degree of inhibition of CD25 expression. We concluded that activation of T-lymphocytes results in rapid down-modulation of surface CD3, CD4 and CD8 followed by re-expression which is inhibited in the case of CD4, but not CD8, by dexamethasone and cyclosporine A. Since CD4 is thought to co-operate in T-lymphocyte antigen recognition by the CD3-antigen receptor complex, this effect may contribute to the immunosuppressive effect of these drugs on CD4 T-lymphocytes.
Haczku
A F
AF
Department of Allergy and Clinical Immunology, National Heart & Lung Institute, London, U.K.
Kay
A B
AB
Corrigan
C J
CJ
D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000187:drug effects; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D003907:Dexamethasone; D016572:Cyclosporine