CD8 coreceptor extinction in signaled CD4(+) CD8(+) thymocytes: Coordinateroles for both transcriptional and posttranscriptional regulatory mechanisms in developing thymocytes

T-cell development in the thymus is characterized by changing expression pa tterns of CD4 and CD8 coreceptor molecules and by changes in CD4 and CD8 ge ne transcription. In response to T-cell receptor (TCR) signals, thymocytes progress through developmental transitions, such as conversion of CD4(+)CD8 (+) (double-positive [DP]) thymocytes into intermediate CD4(+)CD8(-) thymoc ytes, that appear to require more-rapid changes in coreceptor expression th an can be accomplished by transcriptional regulation alone. Consequently, w e considered the possibility that TCR stimulation of DP thymocytes not only affects coreceptor gene transcription but also affects coreceptor RNA stab ility. Indeed, we found that TCR signals in DP thymocytes rapidly destabili zed preexisting CD4 and CD8 coreceptor RNAs, resulting in their rapid elimi nation. Destabilization of coreceptor RNA was shown for CD8 alpha to be dep endent on target sequences in the noncoding region of the RNA. TCR signals also differentially affected coreceptor gene transcription in DP thymocytes , terminating CD8 alpha gene transcription but only transiently reducing CD 4 gene transcription. Thus, posttranscriptional and transcriptional regulat ory mechanisms act coordinately in signaled DP thymocytes to promote the ra pid conversion of these cells into intermediate CD4+CD8- thymocytes. We sug gest that destabilization of preexisting coreceptor RNAs is a mechanism by which coreceptor expression in developing thymocytes is rapidly altered at critical points in the differentiation of these cells.