In response to suboptimal activation, T cells become hyporesponsive, with a severely reduced capacity to proliferate and produce cytokines upon reencounter with antigen. Chromatin analysis of T cells made tolerant by use of different in vitro and in vivo approaches reveals that the expression of gamma interferon (IFN-γ) is epigenetically silenced in anergic effector TH1 cells. In those T cells, calcium signaling triggers the expression of Tle4, a member of the Groucho family of corepressors, which is then recruited to a distal regulatory element in the Ifng locus and causes the establishment of repressive epigenetic marks at the Ifng gene regulatory elements. Consequently, impaired Tle4 activity results in a markedly reduced capacity to inhibit IFN-γ production in tolerized T cells. We propose that Blimp1-dependent recruitment of Tle4 to the Ifng locus causes epigenetic silencing of the expression of the Ifng gene in anergic TH1 cells. These results define a novel function of Groucho family corepressors in peripheral T cells and demonstrate that specific mechanisms are activated in tolerant T helper cells to directly repress expression of effector cytokines, supporting the hypothesis that stable epigenetic imprinting contributes to the maintenance of the tolerance-associated hyporesponsive phenotype in T cells.