Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells

Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5138-43. doi: 10.1073/pnas.0501675102. Epub 2005 Mar 24.

Abstract

Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized over-production of cytokines. Here, we show that, among the Foxp transcriptional factor family, which includes Foxp1, Foxp2, and Foxp3, only Foxp3 has the ability to inhibit IL-2, IL-4, and IFN-gamma production by primary T helper cells. We found that Foxp3 physically associates with the Rel family transcription factors, nuclear factor of activated T cells (NFAT) and NF-kappaB, and blocks their ability to induce the endogenous expression of their target genes, including key cytokine genes. More importantly, T cells derived from scurfy mice have a dramatic increase in nuclear factor of activated T cells (NFAT) and NF-kappa B transcriptional activity compared with the T cells derived from WT mice. Furthermore, complementation of Foxp3 in scurfy-derived T cells lowers the NFAT and NF-kappa B transcriptional activity to the physiological level. Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells. Foxp3 has already been associated with the generation of CD4(+)CD25+ regulatory T cells; our data additionally demonstrate that Foxp3 suppresses the effector functions of T helper cells by directly inhibiting the activity of two key transcription factors, NFAT and NF-kappa B, which are essential for cytokine gene expression and T cell functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoimmunity
  • Cell Line
  • Cytokines / biosynthesis
  • Cytokines / genetics*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Forkhead Transcription Factors
  • Gene Expression
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / genetics
  • Jurkat Cells
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors
  • Nuclear Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Activation

Substances

  • Cytokines
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • NF-kappa B
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors
  • Interleukin-4
  • Interferon-gamma