Converting antigen-specific diabetogenic CD4 and CD8 T cells to TGF-beta producing non-pathogenic regulatory cells following FoxP3 transduction

J Autoimmun. 2007 Jun;28(4):188-200. doi: 10.1016/j.jaut.2007.02.015. Epub 2007 Apr 6.

Abstract

Immuno-regulatory defects, including a reduction in the number and function of regulatory T cells, play an important role in the development of autoimmune diabetes in both humans and non-obese diabetic (NOD) mice. In this study we tested the effect of introduction of FoxP3 into antigen non-specific polyclonal and antigen-specific monoclonal T cells on diabetes development in NOD mice. Transduction of FoxP3 into antigen-specific monoclonal (insulin or BDC2.5 mimotope specific) or antigen non-specific polyclonal T cells using retroviral transduction delayed or prevented diabetes development. However, transduced antigen-specific monoclonal T cells were considerably more effective than polyclonal T cells. Regulatory activity was not limited to CD4 T cells as potent diabetogenic CD8 T cells specific for insulin, were also reduced in pathogenicity by FoxP3 induction. The disease suppressive effect, in both CD4 and CD8 cells, was more evident in spontaneously diabetes-prone NOD hosts (non-lymphopenic) than in lymphopenic NOD.scid hosts. We suggest that this strategy of transducing antigen-specific CD4 or CD8 T cells may be a useful therapeutic approach in the prevention of autoimmune diabetes.

Publication types

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

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Genetic Therapy
  • Insulin / immunology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Retroviridae
  • Transduction, Genetic
  • Transforming Growth Factor beta / immunology*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Insulin
  • Transforming Growth Factor beta