Two Lysines in the Forkhead Domain of Foxp3 are Key to T Regulatory Cell Function

The forkhead transcription factor, Foxp3, is pivotal to the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. Previous data indicated that many of the functions of Foxp3 are controlled by the acetylation of several lysines within the forkhead domain. We now show that mutation of each of two lysines within the forkhead domain of Foxp3, lysine at position 382 (K17) and lysine at position 393 (K18), impaired Treg suppressive function in vivo and in vitro. Lysine mutations also decreased Treg expression of multiple functionally important Foxp3-regulated genes, and inhibited the promoter remodeling of target genes (CTLA-4 and IL-2) without affecting Foxp3 expression level. These data point to the need for a further understanding of the effects of various post-translational modifications on Foxp3 function. Our studies also provide a rationale for developing small molecule inhibitors of such post-translational modifications so as to regulate Foxp3+ Treg function clinically.