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In This Issue, The Journal of Immunology, Volume 180, Issue 7, April 2008, Pages 4349–4350, https://doi.org/10.4049/jimmunol.180.7.4349
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FoxP3 Interaction with RORα
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The molecular mechanisms that regulatory T cells (Tregs) use to suppress immune responses are still unclear. Humans express at least two isoforms of transcription factor forkhead box 3 (FoxP3) in Tregs, a full-length form and a splice variant lacking exon 2, both of which are equally induced upon CD4+CD25− T cell stimulation. Using a yeast two-hybrid screen, Du et al. (p. 4785 ) determined that part of FoxP3 transcriptional suppression is mediated through its interaction with the retinoic acid receptor-related orphan receptor (RORα). FoxP3 and RORα colocalized in the nucleus of transfected cells, but the full-length form of FoxP3 was necessary for interaction with RORα. Without the LxxLL motif located in exon 2 of the FoxP3 transcript or the AF2 motif in RORα, there was no interaction with RORα and transcriptional repression by FoxP3 was abolished. FoxP3 transcriptional control was not dependent on DNA binding, as loss of the forkhead binding domain had no effect. RORα regulates the expression of Th17-type cytokines in T cells such as IL-17, IL-22, and CXCR3, the transcription of which were repressed by expression of full-length FoxP3. The authors have executed an elegant study demonstrating an important mechanism by which FoxP3 mediates immune regulation.
