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

Nat Med. 2003 Sep;9(9):1202-8. doi: 10.1038/nm924. Epub 2003 Aug 24.


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 CD3epsilon-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)-beta-specific antibody. The central role of TGF-beta 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-beta-producing regulatory CD4+ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antigens, CD
  • Antigens, Differentiation / immunology
  • CD3 Complex / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Interleukin-2 / immunology
  • Receptors, Interleukin-2 / metabolism
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*


  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation
  • CD3 Complex
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Receptors, Interleukin-2
  • Transforming Growth Factor beta