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, β and γ , are critical in the development of pathogenic effector T cells. CD4 + T cells lacking Gadd45 β 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 Gadd45 β and Gadd45 γ spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45 β /Gadd45 γ -mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.