SYNERGISTIC INDUCTION OF CTLA-4 EXPRESSION BY COSTIMULATION WITH TCR PLUS CD28 SIGNALS MEDIATED BY INCREASED TRANSCRIPTION AND MESSENGER-RIBONUCLEIC-ACID STABILITY

T cell activation requires at least two signals transduced by the Ag-s pecific TCR plus a costimulatory receptor. The CD28 costimulatory mole cule has been shown to promote T cell proliferation and cytokine produ ction, CTLA-4, a cell surface molecule homologous to CD28, can functio n as a repressor of T cell activation. Thus, CTLA-4 and CD28 may have opposing functions during T cell activation. CTLA-4 is expressed at lo w levels on resting T cells and up-regulated after T cell activation. Regulation of CTLA-4 expression is critical to the normal regulation o f immunity. For example, CTLA-4-deficient mice develop early onset let hal autoimmunity. We previously showed that CTLA-4 transcription is in creased after T cell activation and that induction was controlled by 3 35 bp of CTLA-4 upstream sequence. In this work, we show that cell sur face CTLA-4 expression is increased synergistically by TCR plus CD28 s ignals, Synergistic induction is mediated by two mechanisms: an enhanc ed rate of transcription and increased mRNA stability, In contrast to the regulation of IL-2 and IL-2R expression, which is inhibited by cyc losporin A-, but not rapamycin-dependent signal transduction pathways, CTLA-4 expression is inhibited by either cyclesporin A or rapamycin. Thus, synergistic induction of CTLA-4 expression requires both cyclosp orin A- and rapamycin-dependent signals.