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Since the characterization of CD4⁺CD25⁺ regulatory T (Treg) cells in mice, significant progress has been made in the definitions of the phenotype and the function of human Treg cells in health and in pathological conditions. Recent advances in the field leading to a better molecular definition of Treg subsets in humans and the description of the dynamics of differentiation of Treg cells should bring new insights in the understanding of human chronic systemic autoimmune diseases. How Treg cells are compromised in these diseases is a challenging issue because the elucidation of the mechanisms leading to such anomaly might lead to promising novel therapeutic approaches.