CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles.
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.
Martinez
Xavier
X
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Kreuwel
Huub T C
HT
Redmond
William L
WL
Trenney
Rebecca
R
Hunter
Kara
K
Rosen
Hugh
H
Sarvetnick
Nora
N
Wicker
Linda S
LS
Sherman
Linda A
LA
D000483:Alleles; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics* / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte