Chronic inflammatory diseases often have residual CD8(+) T cell infiltration despite treatment with systemic corticosteroids suggesting divergent steroid responses between CD4(+) vs. CD8(+) cells. To examine steroid sensitivity, dexamethasone (DEX)-induced histone H4 lysine (K)5 acetylation and glucocorticoid receptor (GCR)alpha translocation were evaluated. DEX treatment for 6h significantly induced H4 K5 acetylation in normal CD4(+) cells (p=0.001), but not in CD8(+) cells. DEX responses were functionally impaired in CD8(+) as compared to CD4(+) cells, using MKP-1 (1h) (p=0.02) and IL-10 mRNA (24h) (p=0.004) induction as a read-out of steroid-induced transactivation. Normal DEX-induced GCRalpha nuclear translocation and no significant difference in GCRalpha and GCRbeta mRNA expression were observed in both T cell types. Also, no significant difference in SRC-1, p300 and TIP60 expression was found. However, ATF2 expression was significantly lower in CD8(+) compared to CD4(+) cells (p=0.009). Importantly, inhibition of ATF2 expression by siRNA in CD4(+) cells resulted in inhibition of DEX-induced transactivation in CD4(+) cells. The data indicates refractory steroid-induced transactivation but similar steroid-induced transrepression of CD8(+) cells as compared to CD4(+) cells due to decreased levels of the histone acetyltransferase ATF2.