Abstract
CD25+CD4+ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR, also known as TNFRSF18)—a member of the tumor necrosis factor–nerve growth factor (TNF-NGF) receptor gene superfamily—is predominantly expressed on CD25+CD4+ T cells and on CD25+CD4+CD8− thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25+CD4+ T cell–mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25+CD4+ regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
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Acknowledgements
We thank T. Suda, N. Hosokawa, H. Kubota, and T. Nomura for technical advice; T. Maruyama, M. Matsumoto and K. Ishihara for the reagents and cell lines; E. Moriizumi for histology; and K. Wood, S. Hori and T. Nomura for critically reading the manuscript. Supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture, the Ministry of Human Welfare, Japan Society for the Promotion of Science, and the Organization for Pharmaceutical Safety and Research of Japan. A part of this work was reported at the annual meeting of Japanese Immunology Association on November 14, 2000.
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Web Figure 1.
Staining of CD25+CD4+ T cells with Fab fragments of DTA-1 mAb. CD25+CD4+ T cells stimulated several times with anti-CD3 and IL-2 (as in Fig. 6) were stained with DTA-1 (a,c) or Fab fragments of DTA-1 (b,d) at concentrations of 3 μg/ml (bold lines). FITC-labeled antibody specific for heavy and light chains of rat Ig (a,b) or antibody specific for Fc portion of rat Ig (c,d) was used as the secondary antibody. Staining with the secondary antibody alone is shown as thin line in each figure. (GIF 20 kb)
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Shimizu, J., Yamazaki, S., Takahashi, T. et al. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3, 135–142 (2002). https://doi.org/10.1038/ni759
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DOI: https://doi.org/10.1038/ni759
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