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

Xavier Martinez, Huub T.C. Kreuwel, William L. Redmond, Rebecca Trenney, Kara Hunter, Hugh Rosen, Nora Sarvetnick, Linda S. Wicker, Linda A. Sherman

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34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1677-1685
Number of pages9
JournalJournal of Immunology
Volume175
Issue number3
DOIs
Publication statusPublished - Aug 1 2005

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Martinez, X., Kreuwel, H. T. C., Redmond, W. L., Trenney, R., Hunter, K., Rosen, H., ... Sherman, L. A. (2005). CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles. Journal of Immunology, 175(3), 1677-1685. https://doi.org/10.4049/jimmunol.175.3.1677