The balanced action of cytokines is known to be critical for the maintenance of homeostatic immune responses. Here, we report the development of an inflammatory skin disease involving CD8⁺ T cells, in mice lacking the transcription factor, interferon regulatory factor-2 (IRF-2). CD8⁺ T cells exhibit in vitro hyper-responsiveness to antigen stimulation, accompanied with a notable upregulation of the expression of genes induced by interferon-α/β (IFN-α/β). Furthermore, both disease development and CD8⁺ T cell abnormality are suppressed by the introduction of nullizygosity to the genes that positively regulate the IFN-α/β signaling pathway. IRF-2 may represent a unique negative regulator, attenuating IFN-α/β-induced gene transcription, which is necessary for balancing the beneficial and harmful effects of IFN-α/β signaling in the immune system.