Cell-mediated suppression of human interleukin-2 gene expression at splicing of mRNA

Human IL-2 gene expression is regulated by cell-mediated suppression. Mitogenic stimulation of PBMC induces transient activation of CD8 cells that inhibit expression of this gene. Depletion of CD8 cells elicits marked superinduction of IL-2 mRNA; reintroduction of CD8 cells causes severe inhibition. Moreover, during IL-2 gene induction, splicing of IL-2 precursor transcripts becomes inhibited, resulting in a transient mRNA wave. This block in IL-2 mRNA splicing is relieved by the translation inhibitor, cycloheximide (CHX), which does not stimulate transcription [Gerez et al., J. Biol. Chem. 270, 15569 (1995)]. We show that suppression of IL-2 mRNA expression, whether by CD8 cells, soluble mediators derived from them, or IL-10, is relieved completely by CHX. Hence, suppression involves a CHX-sensitive step. Response to CHX, manifested in superinduction of IL-2 mRNA, is enhanced 10-fold during suppression. Suppression by CD8 cells or soluble mediators leads to rapid degradation of precursor transcripts while relief from suppression leads to a significant rise in precursor RNA. These changes precede effects at the mRNA level. We conclude that suppression induces a block in mRNA splicing and degradation of blocked precursor transcripts. The near-complete absence of IL-2 mRNA superinduction by CHX in Jurkat Th cells, lacking cells with suppressive capacity, supports this interpretation.