Abstract
BackgroundThe 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.Methodology/Principal FindingsWe found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function in vivo and in vitro. These lysine mutations did not affect the level of expression of Foxp3 but inhibited IL-2 promoter remodeling and had important and differing effects on Treg-associated gene expression.Conclusions/SignificanceThese 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.
Highlights
CD4+CD25+ T-regulatory (Treg) cells are important to the maintenance of immunological homeostasis and self-tolerance [1,2]
Mutations within the FKH domain that disrupt the interaction of Foxp3 and NFAT result in loss of the ability of Foxp3 to downregulate IL-2 expression and upregulate CTLA4 and CD25 expression [13]
Wild-type mouse Foxp3 (WT-Foxp3) or mouse Foxp3 constructs containing mutated K16-19R or K1619Q were cloned into a retroviral vector (MinR1) encoding nonfunctional nerve growth factor receptor (NGFR), MinR1 constructs were transfected into packaging cell lines, and supernatants from packaging cell lines were used to infect activated mouse primary CD4+ T cells
Summary
CD4+CD25+ T-regulatory (Treg) cells are important to the maintenance of immunological homeostasis and self-tolerance [1,2]. The forkhead box transcription factor, Foxp, is recognized as the master regulator of the development and function of CD4+CD25+ Treg cells [3,4,5]. Murine and human Foxp protein share a high degree of homology, with 429 and 431 amino acids, respectively Both proteins contain a repressor domain, a zinc finger domain, a leucine zipper domain, and a conserved DNA binding C-terminal forkhead domain (FKH) important for the nuclear translocation and DNA binding of Foxp3 [7,8]. A single glutamic acid mutation (E251) or deletion of E250 in the leucine-zipper domain inhibited Foxp dimerization and abrogated its repressor functions [7,15]. The forkhead box transcription factor, Foxp, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. We assessed how individual FKH lysines contribute to the functions of Foxp in Treg cells
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