International Immunology Advance Access originally published online on June 22, 2007
International Immunology 2007 19(7):825-835; doi:10.1093/intimm/dxm043
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FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease
1 Department of Pathology and Laboratory Medicine, University of Pennsylvania, 252 John Morgan Building, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA
2 Department of Pediatrics, The David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
3 Monoclonal Antibodies Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
4 Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK
Correspondence to: M. I. Greene; E-mail: greene{at}reo.med.upenn.edu
We have found that FOXP3 is an oligomeric component of a large supramolecular complex. Certain FOXP3 mutants with single amino acid deletions in the leucine zipper domain of FOXP3 are associated with the X-linked autoimmunity-allergic dysregulation (XLAAD) and immunodysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX) syndrome in humans. We report that the single amino acid deletion found in human XLAAD/IPEX patients within the leucine zipper domain of FOXP3 does not disrupt its ability to join the larger protein complex, but eliminates FOXP3 homo-oligomerization as well as heteromerization with FOXP1. We found that the zinc finger–leucine zipper domain region of FOXP3 is sufficient to mediate both homodimerization and homotetramerization. However, the same domain region from XLAAD/IPEX FOXP3 containing an E251 deletion prevents oligomerizaton and the protein remains monomeric. We also found that wild-type FOXP3 directly binds to the human IL-2 promoter, but the E251 deletion in FOXP3 in XLAAD/IPEX patient's T cells disrupts its association with the IL-2 promoter in vivo and in vitro, and limits repression of IL-2 transcription after T-cell activation. Our results suggest that compromising FOXP3 homo-oligomerization and hetero-oligomerization with the FOXP1 protein impairs DNA-binding properties leading to distinct biochemical phenotypes in humans with the XLAAD/IPEX autoimmune syndrome. This study explains some features of the pathogenesis of a disease syndrome that arises as a consequence of specific assembly failure of a transcriptional repressor due to certain mutations within the FOXP3 leucine zipper.
Keywords: FOXP3, IPEX, oligomerization, regulatory T cell, XLAAD
Transmitting editor: T. Hamaoka
Received 15 February 2007, accepted 19 March 2007.
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