DNA demethylation and histone hyperacetylation of CD11a and CD70 regulatory regions contribute to the development of autoreactivity and autoantibody overstimulation in CD4⁺ T cells of patients with systemic lupus erythematosus (SLE). However, the mechanisms causing these changes remain largely unknown. We report that the expression and activity of the transcription factor RFX1 are decreased in SLE CD4⁺ T cells. We demonstrate that RFX1 affects DNA methylation and histone acetylation in CD4⁺ T cells by recruiting the co-repressors DNMT1 and HDAC1 to the CD11a and CD70 promoters, and thereby represses their expression. Reducing RFX1 in CD4⁺ T cells is sufficient to cause lupus-like T and B cell hyperactivity, whereas overexpressing RFX1 suppresses T cell reactivity. These findings reveal a crucial role for RFX1 in regulating the epigenetic status of T cells, and demonstrate that autoimmune responses in SLE are due in part to RFX1 downregulation.