T-CELL RECEPTOR (TCR) ENGAGEMENT LEADS TO ACTIVATION-INDUCED SPLICINGOF TUMOR-NECROSIS-FACTOR (TNF) NUCLEAR PRE-MESSENGER-RNA

Inducible gene expression is primarily regulated at the level of trans cription. Additional steps of ''processing'' pre-mRNA, involved in the regulation of induced gene expression, have not been previously repor ted. Here we report a novel mechanism of ''activation-induced splicing '' of preexisting tumor necrosis factor (TNF) message (pre-mRNA) in na ive T lymphocytes after engagement of the T cell receptor (TCR), which still occurs after inhibition of transcription. Expression of TNF has been previously demonstrated to be regulated at both the transcriptio nal and translational levels. However, neither the large pool of TNF m RNA observed in activated T cells nor TNF protein production, which pe aks very shortly after activation, can be solely attributed to increas ed transcription. Evidence is presented that activation-induced splici ng of TNF pre-mRNA plays a significant role in the rapid production of TNF seen in activated T cells. Activation triggers processing of TNF pre-mRNA that has accumulated in naive T cells (before activation-indu ced transcription), and the mature TNF mRNA is translocated to the cyt oplasm for rapid translation and protein production. This novel form o f activation-induced splicing of TNF may allow T cells to mount an imm ediate response to activation stimuli-under physiological conditions.