Autoimmune Diabetes Onset Results From Qualitative Rather Than Quantitative Age-Dependent Changes in Pathogenic T-Cells

  1. Sylvaine You12,
  2. Mériam Belghith12,
  3. Stephen Cobbold3,
  4. Marie-Alexandra Alyanakian12,
  5. Christine Gouarin12,
  6. Samia Barriot12,
  7. Corinne Garcia2,
  8. Herman Waldmann3,
  9. Jean-François Bach12 and
  10. Lucienne Chatenoud12
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM) U580, Paris, France
  2. 2Faculté de Medicine, René Descartes Paris 5, Paris, France
  3. 3Sir William Dunn School of Pathology, Oxford, U.K
  1. Address correspondence and reprint requests to Pr. Lucienne Chatenoud, INSERM U580, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. E-mail: chatenoud{at}necker.fr

Abstract

Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-β–dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-β–dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell’s escape from TGF-β–dependent T-cell–mediated regulation.

Footnotes

    • Accepted February 10, 2005.
    • Received October 6, 2004.
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