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Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4FOXP3 regulatory T cells (T) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long , which led to destabilization of forkhead box P3 (FOXP3) and T dysfunction. This aberrant axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of expression and T dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T in autoimmune diseases.