Histone acetylation as an epigenetic mediator of human T cell memory: Memory T cells differentiate from naive T cells after encountering antigen, acquiring the ability to mount a more rapid and robust response to antigen than their naive precursors. To understand the molecular basis for the robust memory T cell responses, gene expression and histone H3 lysine 9 (H3K9) acetylation levels were compared between naive and memory CD8+ T cells. Approximately half of the genes that are more highly expressed in memory CD8+ T cells than in naive CD8+ T cells had higher H3K9 acetylation levels in their promoter region in memory CD8+ T cells than those in naive CD8+ T cells. Strikingly, close to half of the genes that are selectively up-regulated after activation of CD8+ memory T cells had higher H3K9 acetylation levels in memory cells prior to activation (in resting memory cells) than in the corresponding resting naive CD8+ T cells. Furthermore, inhibition of histone deacetylase results in an increase of H3K9 acetylation levels in naive cells and consequently an increased expression in 80% of these genes. These findings suggest that histone H3K9 hyperacetylation is responsible for the ability of resting memory T cells to respond to antigen re-exposure with the rapid and selective program of gene expression that is characteristic of the memory T cell response. Gene expression characteristics of CD28- memory phenotype CD8+ T cells and its implication in T cell aging: Accumulation of CD28-CD8+ T cells is considered as one of the hallmarks of aging in the human immune system. However, the precise changes of CD28nullCD8+ T cells as compared to the precursor CD28+CD8+ memory T cells have not been determined. Here, we present an analysis of the global gene expression profiles of CD28+ and CD28- memory phenotype CD8+ T cells. These two CD8+ T subsets exhibited an overall similar gene expression profile with only a few dozen genes that were differentially expressed. A wide range of functions including co-stimulation, effector activity, signaling, and transcription were possessed by these differentially expressed genes, reflecting significant functional changes of CD28- memory phenotype CD8+ T cells from their CD28+ counterparts. In addition, CD28null memory CD8+ T cells expressed several different NK cell receptors and high levels of granzymes, perforin, and FasL, indicating an increasing capacity for cytotoxicity during memory CD8+ T cell aging. Interestingly, in vitro culture of these two subsets with interleukin 15 (IL-15) revealed that similar gene expression changes occurred in both subsets. Our analysis provides the gene expression portraits of CD28null memory phenotype CD8+ T cells and alteration from their CD28+ counterparts and suggests potential mechanisms of T cell aging.
