Cd8 enhancer E8 _Iand Runx factors regulate CD8α expression in activated CD8 ⁺ T cells

Cd8a and Cd8b1 coreceptor gene (Cd8) expression is tightly controlled during T-cell development by the activity of five Cd8 enhancers (E8 _I-E8 _V). Here we demonstrate a unique transcriptional program regulating CD8 expression during CD8 ⁺ effector T-cell differentiation. The Cd8 enhancer E8 _I and Runx/core-binding factor-β (CBFβ) complexes were required for the establishment of this regulatory circuit, because E8 _I-, Runx3-, or CBFβ-deficient CD8 ⁺ T cells down-regulated CD8α expression during activation. This finding correlated with enhanced repressive histone marks at the Cd8a promoter in the absence of E8 _I, and the down-regulation of CD8α expression could be blocked by treating E8 _I-, Runx3-, or CBFβ- deficient CD8 ⁺ T cells with the histone deacetylase inhibitor trichostatin A. Moreover, Runx/CBFβ complexes bound the Cd8ab gene cluster in activated CD8 ⁺ T cells, suggesting direct control of the Cd8a locus. However, CD8 ⁺ effector T cells maintained high levels of CD8α when CBFβ was conditionally deleted after activation. Thus, our data suggest an E8 _I- and Runx3/CBFβ-dependent epigenetic programming of the Cd8a locus during T-cell activation, leading to Runx/ CBFβ complex-independent maintenance of CD8α expression in effector T cells.