Downstream Regulatory Element Antagonist Modulator (DREAM) is a Ca²⁺‐dependent transcriptional repressor expressed in the brain, thyroid gland and thymus. Here, we analyzed the function of DREAM and the related protein KChIP‐2 in the immune system using transgenic (tg) mice expressing a cross‐dominant active mutant (EFmDREAM) for DREAM and KChIPs Ca²⁺‐dependent transcriptional derepression. EFmDREAM tg mice showed reduced T‐cell proliferation. Tg T cells exhibited decreased interleukin (IL)‐2, ‐4 and interferon (IFN)γ production after polyclonal activation and following antigen‐specific response. Chromatin immunoprecipitation and transfection assays showed that DREAM binds to and represses transcription from these cytokine promoters. Importantly, specific transient knockdown of DREAM or KChIP‐2 induced basal expression of IL‐2 and IFNγ in wild‐type splenocytes. These data propose DREAM and KChIP‐2 as Ca²⁺‐dependent repressors of the immune response.