Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8(+) T cells

Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-alpha, IFN-gamma, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8(+) T cells. We show that the immediate and ample production of TNF-alpha is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-gamma uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-gamma, and of IL-2, depends on calcium-induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specificmanner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time