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TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes

Nature Medicine volume 9, pages 1202–1208 (2003)Cite this article

Abstract

CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3ε-specific antibodies induces transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28−/− mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-β-specific antibody. The central role of TGF-β was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-β-producing regulatory CD4+ T cells.

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Figure 1: CD4+CD25+ lymphocytes in CD3-specific antibody–treated NOD mice.
Figure 2: Remission of established diabetes in antibody-treated NOD Cd28−/− mice.
Figure 3: CD4+CD25+ lymphocytes from antibody-treated NOD mice are suppressive in vitro.
Figure 4: TGF-β is produced by CD4+ lymphocytes from CD3-specific antibody–treated mice.
Figure 5: Prevention and reversal of CD3-specific antibody–induced tolerance by an antibody to CTLA-4.

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Acknowledgements

This work was supported by grants from INSERM, Association Claude Bernard and Juvenile Diabetes Research Foundation. The authors thank I. Cisse, F. Valette and M. Garcia for managing the animal facility; M. Netter for iconography; C. Garcia for assistance with FACS sorting; M. de la Torre for editing of the manuscript; W. Paul, A. O'Garra and S. Cobbold for providing the monoclonal antibodies used in this study; and D. Mathis and C. Benoist for providing the NOD Il4−/− mice.

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Authors and Affiliations

  1. INSERM U580, IRNEM, Hôpital Necker, 161 Rue de Sèvres, Paris, 75015, France

    Mériam Belghith, Samia Barriot, Jean-François Bach & Lucienne Chatenoud

  2. Diabetes Center and Department of Medicine, University of California, San Francisco, 94143, California, USA

    Jeffrey A Bluestone

  3. IRNEM, Faculté Necker Enfants Malades, Hôpital Necker, 161 Rue de Sèvres, Paris, 75015, France

    Jérôme Mégret

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  1. Mériam Belghith
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Correspondence to Lucienne Chatenoud.

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Belghith, M., Bluestone, J., Barriot, S. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9, 1202–1208 (2003). https://doi.org/10.1038/nm924

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