Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells

Int Immunol. 2004 Nov;16(11):1643-56. doi: 10.1093/intimm/dxh165. Epub 2004 Oct 4.


Naturally occurring CD25(+)CD4(+) regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25(+)CD4(+) regulatory T cells. Here we examined the role of FOXP3 in human CD25(+)CD4(+) regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25(+)CD4(+) T cells, in particular CD25(+)CD45RO(+)CD4(+) T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25(-)CD45RO(-)CD4(+) naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25(-)CD45RO(-)CD4(+) naive T cells into a regulatory T cell phenotype similar to CD25(+)CD4(+) regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell-cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25(+)CD4(+) regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/inflammatory diseases and negative control of various immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / therapy
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Forkhead Transcription Factors
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Genetic Therapy
  • Humans
  • Immune Tolerance*
  • Receptors, Interleukin-2 / immunology*
  • Transduction, Genetic


  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Receptors, Interleukin-2