International Immunology Advance Access originally published online on June 13, 2006
International Immunology 2006 18(8):1197-1209; doi:10.1093/intimm/dxl060
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Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis
1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
2 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Correspondence to: S. Sakaguchi; E-mail: shimon{at}frontier.kyoto-u.ac.jp
Naturally occurring CD25+CD4+ regulatory T cells (Tregs) actively engage in the maintenance of immunologic self-tolerance and immunoregulation. They specifically express the transcription factor Forkhead box P3 (Foxp3) as a master control molecule for their development and function. Although several cell-surface molecules have been reported as Treg-specific markers, such as CD25, glucocorticoid-induced TNFR family-related gene/protein and CTL-associated molecule-4, they are also expressed on activated T cells derived from CD25–CD4+ naive T cells. To identify Treg-specific molecules controlled by Foxp3, we performed DNA microarray analysis by comparing the following pairs of cell populations: fresh CD25+CD4+ T cells versus fresh CD25–CD4+ T cells, activated CD25+CD4+ T cells versus activated CD25–CD4+ T cells and retrovirally Foxp3-transduced CD25–CD4+ T cells versus mock-transduced CD25–CD4+ T cells. We found that the Gpr83, Ecm1, Cmtm7, Nkg7, Socs2 and glutaredoxin genes are predominantly transcribed in fresh and activated natural Treg as well as in Foxp3-transduced cells, while insulin-like 7, galectin-1, granzyme B and helios genes are natural Treg specific but Foxp3 independent. G protein-coupled receptor 83 (Gpr83) expression on the cell surface of natural Treg was confirmed by staining with Gpr83-specific antibody. Retroviral transduction of either group of genes in CD25–CD4+ T cells failed to confer in vitro suppressive activity. Thus, there are several genes that are expressed in a highly Treg-specific fashion. Some of these genes are controlled by Foxp3, and others are not. These genes, in particular, Gpr83, Ecm1 and Helios, could potentially be used as specific markers for natural Treg.
Keywords: Ecm1, galectin-1, Gpr83, helios, immune tolerance
* These authors contributed equally to this work.
Transmitting editor: K. Yamamoto
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