The normal thymus produces FOXP3-expressing CD25⁺CD4⁺ T_R cells. Some of the naive CD25^–CD4⁺ T cells may also differentiate to FOXP3-expressing CD25⁺CD4⁺ T_R cells in the periphery. These T_R cells suppress the activation and expansion of self-reactive T cells that may cause autoimmune disease. Genetic defects of FOXP3 cause IPEX due to developmental or functional defects of T_R cells. Adapted with permission from Nature Immunology (21).