SOCS_1 is a cytokine-inducible, negative regulatory molecule of JAKs and its deficiency causes hyper-response to various cytokines. SOCS_1^-/- mice spontaneously develop a fatal disease depending on aberrantly activated lymphocytes. Here, we show that partial restoration of SOCS_1 in lymphoid cells rescues SOCS_1^-/- mice from the early-onset fatal disease, indicating that SOCS_1 expression in vivo is especially required in lymphocytes. However, SOCS_1 expression in these SOCS_1-restored mutant mice (Eμ-SOCS_1^-/- mice) was insufficient for proper down-regulation of its target signaling, and these mice spontaneously exhibit hyperactivation of lymphocytes, an increase in the levels of serum immunoglobulins and anti-DNA autoantibodies, and glomerulonephritis with glomerular IgG deposition. These phenotypes resemble those of murine systemic autoimmune diseases, models for systemic lupus erythematosus. Interestingly, similar phenotypes were also observed in adult female SOCS_1^+/- mice, indicating that the autoimmune phenotypes of these mice can be ascribed primarily to the inadequate expression of SOCS_1. In addition, autoimmune phenotypes were not observed in SOCS_1^+/-CD4^-/- mice, suggesting that autoimmunity is dependent on hyper-activated CD4⁺ T cells. Our findings also suggest that insufficient expression of SOCS_1 results in impaired function of CD4⁺CD25⁺ regulatory T cells, which may contribute to aberrant activation of CD4⁺ T cells. These findings suggest that dysfunction of SOCS_1 can be a pathogenic factor of systemic autoimmune diseases such as SLE.