Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells

In T cells anergy may be evoked by an unbalanced stimulation of the T-cell receptor in the absence of costimulation. Anergic T cells are unresponsive to new antigen receptor engagement and do not produce interleukin 2. We present evidence that anergizing stimuli induce changes in histone acetylation, which mediates transcriptional repression of interleukin 2 expression. In response to calcium signaling, anergic T cells up-regulate the expression of lkaros, a zinc finger transcription factor essential for lymphoid lineage determination. lkaros binds to the interleukin 2 promoter where it induces histone deacetylation. Confirming the role of lkaros in the induction of T-cell anergy, cells with reduced lkaros activity show defective inactivation in response to an anergizing stimulus. We propose a model in which tolerizing stimuli induce epigenetic changes on the interleukin 2 locus that are responsible for the stable inhibition of the expression of this cytokine in anergic T cells.