DNA methylation and the expanding epigenetics of T cell lineage commitment

During their development from progenitors, lymphocytes make a series of cell fate decisions. These decisions reflect and require changes in overall programs of gene expression. To maintain cellular identity, programs of gene expression must be iterated through mitosis in a heritable manner by epigenetic processes, which include DNA methylation, methyl-CpG-binding proteins, histone modifications, transcription factors and higher order chromatin structure. Current evidence is consistent with the notion that DNA methylation acts in concert with other epigenetic processes to limit the probability of aberrant gene expression and to stabilize, rather than to initiate, cell fate decisions. In particular, DNA methylation appears to be a non-redundant repressor of CD8 expression in TCR-gammadelta T cells and Th2 cytokine expression in Th1 and CD8 T cells, and is required to enforce clonally restricted Ly49 and KIR gene expression in NK cells. However, most of our knowledge is derived from in vitro studies, and the importance of DNA methylation in memory cell lineage fidelity in vivo remains to be shown convincingly.