FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease

Int Immunol. 2007 Jul;19(7):825-35. doi: 10.1093/intimm/dxm043. Epub 2007 Jun 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Deletion*
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Syndrome
  • T-Lymphocytes / immunology
  • Transcription, Genetic


  • FOXP1 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Multiprotein Complexes
  • Repressor Proteins