Abstract
BackgroundSevere autoinflammatory diseases are associated with mutations in the Foxp3 locus in both mice and humans. Foxp3 is required for the development, function, and maintenance of regulatory T cells (Tregs), a subset of CD4 cells that suppress T cell activation and inflammatory processes. Siva is a pro-apoptotic gene that is expressed across a range of tissues, including CD4 T cells. Siva interacts with three tumor necrosis factor receptor (TNFR) family members that are constitutively expressed on Treg cells: CD27, GITR, and OX40.ResultsHere 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.ConclusionsIn 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.
Highlights
Severe autoinflammatory diseases are associated with mutations in the Foxp3 locus in both mice and humans
Siva regulates T cell apoptosis and, second, because Siva associates with tumor necrosis factor receptor (TNFR) family members that might contribute to Treg function: CD27, GITR, and OX40 [29,30,31,32,33]
Siva-2 lacks the second exon, resulting in a protein that is missing most of the spherical amphipathic helix (SAH) and death domain homology region (DDHR) [28]
Summary
Severe autoinflammatory diseases are associated with mutations in the Foxp locus in both mice and humans. Foxp is required for the development, function, and maintenance of regulatory T cells (Tregs), a subset of CD4 cells that suppress T cell activation and inflammatory processes. The transcription factor Foxp 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 Foxp in both mice and humans led to its initial identification [2,3]. Foxp activates and suppresses a broad range of genes, but the mechanisms by which this happens are not well-understood [8,9,10].
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