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Persistent T cell anergy in human type 1 diabetes.

H Dosch1, R K Cheung, W Karges

  • 1Department of Pediatrics, University of Toronto, The Hospital For Sick Children, Research Institute, Toronto, Ontario, Canada. hmdosch@sickkids.on.ca

Journal of Immunology (Baltimore, Md. : 1950)
|December 10, 1999
PubMed
Summary

Type 1 diabetes involves anergic T cells that persist for decades, requiring less IL-2 and resisting apoptosis. These findings impact immunotherapy and islet transplantation strategies for diabetes.

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Area of Science:

  • Immunology
  • Endocrinology
  • Autoimmunity

Background:

  • Anergic T cells are observed in type 1 diabetes (T1D) models and patients.
  • Understanding T cell anergy is crucial for T1D pathogenesis and treatment.

Purpose of the Study:

  • To investigate T cell proliferative responses and anergy in new-onset and longstanding type 1 diabetes.
  • To characterize the persistence and features of autoreactive T cells in T1D.

Main Methods:

  • Measured T cell proliferation to diabetes-associated antigens in 148 new diabetic children, 51 siblings, 31 long-standing patients, and 40 controls.
  • Assessed responses to glutamate decarboxylase of 65 kDa (GAD65), islet cell cytoplasmic autoantibody (ICA) 69, and others, with and without exogenous IL-2.
  • Evaluated T cell apoptosis resistance and cytokine production.

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Main Results:

  • Most patients and siblings showed anergic T cell responses to GAD65, ICA69, and Hsp60, requiring IL-2.
  • Proinsulin and IA-2 responses were non-anergic and rescued anergic cells.
  • 85% of new patients had multiple autoreactive T cells, a hallmark of overt disease, persisting for years.
  • Diabetic T cells exhibited high resistance to apoptosis, needing significantly less IL-2.

Conclusions:

  • Diabetic T cell anergy is a persistent, antigen-specific phenomenon lasting decades.
  • Autoreactive T cells in T1D show unique resistance to apoptosis and altered IL-2 dependence.
  • These characteristics present challenges for T1D immunotherapy and islet transplantation.