Chromatin-based regulatory mechanisms governing cytokine gene transcription

On initial contact with antigen, naive T cells differentiate and acquire effector characteristics, including the ability to transcribe specific cytokine genes rapidly and at high levels on subsequent exposure to antigen. Several effector T-cell subsets showing distinct patterns of cytokine gene transcription have been described. The patterns of cytokine expression in response to pathogenic challenges have a significant impact on the outcome of immune and inflammatory reactions. Here we review recent studies suggesting that the ability of naive T cells to differentiate into specific cytokine-expressing cells is regulated by epigenetic changes in the accessibility and chromatin structure of cytokine genetic loci. Antigen and cytokine stimulation of naive T cells activates diverse intracellular signaling pathways, which result in chromatin remodeling and demethylation of cytokine genes. These changes are likely to increase, in a stable and heritable fashion, the accessibility of these genes to the basal transcriptional machinery. Chromatin-based regulatory mechanisms may explain several features of cytokine gene expression in effector versus naive T cells, including their monoallelic expression, coordinate regulation, and stable maintenance in memory T cells. The hypothesis of epigenetic changes occurring during T-cell differentiation provides a framework for a comprehensive understanding of cytokine expression by T cells.