Inhibition of activation‐induced changes in the structure of the T cell interleukin‐7 receptor by cyclosporin A and FK506

Abstract

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.