Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.
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.
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Haruhiko
H
Yagi
Takashi
T
Nomura
Kyoko
K
Nakamura
Sayuri
S
Yamazaki
Toshio
T
Kitawaki
Shohei
S
Hori
Michiyuki
M
Maeda
Masafumi
M
Onodera
Takashi
T
Uchiyama
Shingo
S
Fujii
Shimon
S
Sakaguchi
D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy; D006801:Humans; D007108:Immune Tolerance; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D014161:Transduction, Genetic
D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015375:Receptors, Interleukin-2