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

<div><h3>Background</h3><p>The forkhead box transcription factor, Foxp3, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. The carboxyl-terminal forkhead (FKH) domain is required for the nuclear localization and DNA binding of Foxp3. We assessed how individual FKH lysines contribute to the functions of Foxp3 in Treg cells.</p> <h3>Methodology/Principal Findings</h3><p>We found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function <em>in vivo</em> and <em>in vitro</em>. These lysine mutations did not affect the level of expression of Foxp3 but inhibited <em>IL-2</em> promoter remodeling and had important and differing effects on Treg-associated gene expression.</p> <h3>Conclusions/Significance</h3><p>These data point to complex effects of post-translational modifications at individual lysines within the Foxp3 FKH domain that affect Treg function. Modulation of these events using small molecule inhibitors may allow regulation of Foxp3+ Treg function clinically.</p>