Using NAC1-deficient (−/−) mice, we uncovered a previously unrecognized but important role of NAC1 in triggering autoimmunity and Treg instability and demonstrated that NAC1 contributes to the break of immune tolerance through its negative control of Treg development and function associated with deacetylation and destabilization of FoxP3 protein. This evidence concerns the gene FOXP3 and Autoimmunity.