GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice

J Clin Invest. 1998 Jan 1;101(1):68-73. doi: 10.1172/JCI119878.


Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantigens / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Division
  • Cytotoxicity Tests, Immunologic
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Models, Animal
  • Female
  • Glutamate Decarboxylase / administration & dosage
  • Glutamate Decarboxylase / immunology*
  • H-2 Antigens / immunology
  • Histocompatibility Antigen H-2D
  • Histocompatibility Antigens Class II / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Lymphotoxin-alpha / biosynthesis
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Rats
  • Th1 Cells / immunology*


  • Autoantigens
  • H-2 Antigens
  • H-2K(K) antigen
  • Histocompatibility Antigen H-2D
  • Histocompatibility Antigens Class II
  • Lymphotoxin-alpha
  • Interleukin-4
  • Interferon-gamma
  • Glutamate Decarboxylase