The number of effector T cells is controlled by proliferation and programmed cell death. Loss of these controls on self-destructive effector T cells may precipitate autoimmunity. Here, we show that two members of the growth arrest and DNA damage-inducible (Gadd45) family, beta and gamma, are critical in the development of pathogenic effector T cells. CD4(+) T cells lacking Gadd45beta can rapidly expand and invade the central nervous system in response to myelin immunization, provoking an exacerbated and prolonged autoimmune encephalomyelitis in mice. Importantly, mice with compound deficiency in Gadd45beta and Gadd45gamma spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45beta/Gadd45gamma-mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.