Regulation of IL-2 gene expression by Siva and FOXP3 in human T cells

Here we report a biophysical interaction between FOXP3 and Siva. We mapped the interaction domains to Siva's C-terminus and to a central region of FOXP3. We showed that Siva repressed IL-2 induction by suppressing IL-2 promoter activity during T cell activation. Siva-1's repressive effect on IL-2 gene expression appears to be mediated by inhibition of NFkappaB, whereas FOXP3 repressed both NFkappaB and NFAT activity.In summary, our data suggest that both FOXP3 and Siva function as negative regulators of IL-2 gene expression in Treg cells, via suppression of NFAT by FOXP3 and of NFkappaB by both FOXP3 and Siva. Our work contributes evidence for Siva's role as a T cell signalling mediator in addition to its known pro-apoptotic function. Though further investigations are needed, evidence for the biophysical interaction between FOXP3 and Siva invites the possibility that Siva may be important for proper Treg cell function.The transcription factor Foxp3 is essential for immune system regulation due to its role in the development and function of regulatory T cells (Tregs) [1,2]. The dramatic autoimmune phenotype that is caused by mutated Foxp3 in both mice and humans led to its initial identification [2,3]. In the absence of Foxp3, lethal autoimmunity ensues. Sequencing of the FOXP3 genes from IPEX (Immune polyendocrinopathy, enteropathy, X-linked) patients revealed function ablating mutations throughout domains critical for FOXP3 function [4,5]. The scurfy mouse is an autoimmune mutant that has a spontaneous truncation mutation in Foxp3. In addition to its well-studied role in Tregs, an emerging body of work has revealed Foxp3 to be a tumor suppressor in breast cancer [6,7]. Foxp3 activates and suppresses a broad range of genes, but the mechanisms by which this happens are not well-understood [8-10]. By understanding the relationship between FOXP3 and its binding partners, we hope to illuminate how FOXP3 operates as a powerful regulator of immune activation.Already, FOXP