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CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles

Academic Article
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Overview

related to degree

  • Redmond, William, Ph.D. in Biology, Scripps Research 1999 - 2004

authors

  • Martinez, X.
  • Kreuwel, H. T. C.
  • Redmond, William
  • Trenney, R.
  • Hunter, K.
  • Rosen, Hugh
  • Sarvetnick, N.
  • Wicker, L. S.
  • Sherman, Linda

publication date

  • August 2005

journal

  • Journal of Immunology  Journal

abstract

  • Although candidate genes controlling autoimmune disease can now be identified, a major challenge that remains is defining the resulting cellular events mediated by each locus. In the current study we have used NOD-InsHA transgenic mice that express the influenza hemagglutinin (HA) as an islet Ag to compare the fate of HA-specific CD8+ T cells in diabetes susceptible NOD-InsHA mice with that observed in diabetes-resistant congenic mice having protective alleles at insulin-dependent diabetes (Idd) 3, Idd5.1, and Idd5.2 (Idd3/5 strain) or at Idd9.1, Idd9.2, and Idd9.3 (Idd9 strain). We demonstrate that protection from diabetes in each case is correlated with functional tolerance of endogenous islet-specific CD8+ T cells. However, by following the fate of naive, CFSE-labeled, islet Ag-specific CD8+ (HA-specific clone-4) or CD4+ (BDC2.5) T cells, we observed that tolerance is achieved differently in each protected strain. In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation. In contrast, resistance alleles in Idd9 mice do not prevent the accumulation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes, indicating that tolerance occurs at a later checkpoint. These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection.

subject areas

  • Alleles
  • Animals
  • Autoantigens
  • CD8-Positive T-Lymphocytes
  • Cell Movement
  • Clone Cells
  • Diabetes Mellitus, Type 1
  • Epitopes, T-Lymphocyte
  • Immune Tolerance
  • Immunity, Innate
  • Insulin Resistance
  • Islets of Langerhans
  • Lymph Nodes
  • Mice
  • Mice, Congenic
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Pancreas
  • T-Lymphocytes, Regulatory
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 16034108
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Additional Document Info

start page

  • 1677

end page

  • 1685

volume

  • 175

issue

  • 3

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