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Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance

Nature Immunology volume 3, pages 135–142 (2002)Cite this article

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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Figure 1: DTA-1 mAb recognizes GITR.
Figure 2: Expression of GITR on mouse lymphoid cells.
Figure 3: DTA-1 mAb abrogates suppression mediated by CD25+CD4+ T cells or thymocytes.
Figure 4: Effects of antibodies specific for TNFR family proteins on CD25+CD4+ T cell–mediated suppression.
Figure 5: Requirement for an active signal through GITR to CD25+CD4+ regulatory T cells for suppression.
Figure 6: Failure of activated GITRhi T cells derived from CD25−CD4+ T cells to exert suppressive activity.
Figure 7: Development of in vivo and in vitro autoimmunity by eliminating GITRhi T cells or administration of DTA-1.

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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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Author notes

  1. Jun Shimizu and Sayuri Yamazaki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

    Jun Shimizu

  2. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan

    Sayuri Yamazaki, Takeshi Takahashi & Shimon Sakaguchi

  3. Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, 630-0101, Japan

    Yasumasa Ishida

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Correspondence to Shimon Sakaguchi.

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Supplementary information

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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