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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 publication

DOI

10.4049/jimmunol.175.3.1677

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

08/2005

Volume

175

Pages

1677 - 1685

Addresses

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Keywords

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