We showed previously that murine naive CD4⁺ T cells and T_H1 cell clones express the beta2-adrenergic receptor (β₂AR), while T_H2 cell clones do not. We report here that naive CD4⁺ T cells that differentiated for 1–5days under T_H1 driving conditions increased β₂AR gene expression, while cells cultured under T_H2 driving conditions decrease β₂AR gene expression. Chromatin immunoprecipitation revealed that the increase in β₂AR gene expression in T_H1 cells is mediated by an increase in histone 3 (H3) and H4 acetylation, as well as an increase in histone 3 lysine 4 (H3K4) methylation. Conversely, the decrease in β₂AR gene expression in T_H2 cells is mediated by a decrease in H3 and H4 acetylation and a decrease in H3K4 methylation, as well as an increase H3K9 and H3K27 methylation. The histone changes could be detected as early as 3days of differentiating conditions. Genomic bisulfite sequencing showed that the level of methylated CpG dinucleotides within the promoter of the β₂AR gene was increased in T_H2 cells as compared to naive and T_H1 cells. Collectively, these results suggest that epigenetic mechanisms mediate maintenance and repression, respectively, of the β₂AR gene expression in T_H1- and T_H2-driven cells, providing a potential mechanism by which the level of β₂AR expression might be modulated pharmacologically within immune cells and other cell types in which the expression profile may change during a disease process.