Cascade of transcriptional induction and repression during IL-2 deprivation-induced apoptosis

Abstract

Apoptosis of mature T lymphocytes is an essential process for maintaining immune system homeostasis. However, the details of the molecular signaling pathways leading to T cell apoptosis are poorly understood. We used cDNA microarrays containing 15,630 murine genes to study the gene expression profile in T lymphocytes at different time points of IL-2 withdrawal. Comparison of the gene expression profiles revealed that 2% of the genes were affected by cytokine starvation. Interestingly, the apoptotic program rather seems to activate gene expression in the early phase of cell death. On the contrary, transcription was strongly repressed in later stages of apoptosis. Self-organizing map clustering of the 270 differentially expressed transcripts revealed specific temporal expression patterns supporting the idea that IL-2 deprivation triggers a tightly regulated transcriptional program to induce cell death. To validate microarray results, changes in gene expression following IL-2 deprivation were confirmed for selected genes by Northern blot. In addition, the signaling pathways created can explain the molecular events leading to T cell apoptosis, even if the T cell line used in this study might not reflect individual T cell subpopulations expressing different level of IL-2 receptor or IL-2 dependence. Taken together, these results provide novel insights into the temporal regulation of gene expression during T lymphocyte death.