Inhibition of activation-induced changes in the structure of the T cell interleukin-7 receptor by cyclosporin A and FK506.
We have recently shown that activation of T cells causes structural changes in the interleukin-7 receptor (IL-7R) (Foxwell et al. Int. Immunol. 1992, 4: 277). Unactivated cells expressed a receptor characterized as a cross-linked protein of 107-kDa whereas activated cells had reduced levels of this 107-kDa complex and now express a major cross-linked product of 93 kDa. These changes in receptor expression were concomitant with the acquisition of IL-7 growth responsiveness by activated T cells. In this study, the effect of the potent immunosuppressive agents cyclosporin A and FK506 on the activation-induced responsiveness to IL-7-driven proliferation and the concomitant changes in receptor structure have been investigated. Cyclosporin A and FK506 suppressed the expression of the 93-kDa complex and the loss of the 107-kDa complex on activated cells. The presence of exogenous IL-7 inhibited the effects of the drugs on IL-7R structure, allowing expression of the 93-kDa complex. Expression of the 93-kDa complex could also be induced either by ionomycin or phorbol esters. As observed for other T cell activation parameters, only those which induced a calcium signal (ionomycin) but not protein kinase C (phorbol esters) were sensitive to the drugs. In all studies, the expression of the 93-kDa complex correlated with the ability of cells to proliferate to IL-7, and thus these results further support the hypothesis that the 93-kDa form of the IL-7R is required to transmit the cytokine's growth signal. Moreover, these data suggest that activation-induced transcriptional events are required for the expression of the 93-kDa complex and the down-regulation of the 107-kDa complex. As reported for IL-2R and IL-4R, our data also show that the expression of another T cell growth factor receptor is sensitive to the effects of cyclosporin A and FK506. These observations also have important implications for reported cyclosporin A effects on the thymus where IL-7 can act as a growth factor for thymocytes.
Foxwell
B M
BM
Kennedy Institute for Rheumatology-Sunley Division, Hammersmith, London, GB.
Willcocks
J L
JL
Taylor-Fishwick
D A
DA
Kulig
K
K
Ryffel
B
B
Londei
M
M
D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D008213:Lymphocyte Activation; D011971:Receptors, Immunologic / Q000737:chemistry / Q000187:drug effects*; D020395:Receptors, Interleukin-7; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
D015851:Interleukin-7; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; D016572:Cyclosporine; D016559:Tacrolimus