Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice

J Autoimmun. 2008 Jun;30(4):197-206. doi: 10.1016/j.jaut.2007.08.001. Epub 2007 Oct 18.


A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D.

Publication types

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

MeSH terms

  • Animals
  • Autoantigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / immunology
  • Flow Cytometry
  • Glutamate Decarboxylase / immunology*
  • HLA-DR4 Antigen / genetics*
  • Humans
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology*


  • Autoantigens
  • Epitopes, T-Lymphocyte
  • HLA-DR4 Antigen
  • Receptors, Antigen, T-Cell
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2