Regulatory T cells (Tregs) suppress pro-inflammatory immune responses and prevent autoimmune disease. Many types of Tregs have been described, the prototypic in mice defined as CD4 +CD25 +with high expression of the Foxp3 transcription factor. However, Fox P3 is not a reliable marker of human CD4 +CD25 +Tregs and Tregs activated by disease-associated antigens have not been well characterised. By comparing autoantigen-activated CD4 +T-cell clones, we identified CD52 as a marker of suppressor clones. We then showed that high expression of CD52 on antigen-activated T cells identified a unique Treg population in human blood. CD52hi Tregs were not distinguished by markers of CD4 +CD25 +Tregs and did not require cell contact for suppressor function. Following activation by glutamic acid decarboxylase 65 or proinsulin, pancreatic islet autoantigens in type 1 diabetes, generation of CD4 + CD52hi Tregs was reduced in individuals at high risk for type 1 diabetes. Autoantigen-specific Tregs should allow monitoring of autoimmune disease susceptibility and response to immunotherapy, in addition to being directly applicable as a cell therapy for autoimmune disease.