Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice
Christophe M. Filippi, … , Janine E. Oldham, Matthias G. von Herrath
Christophe M. Filippi, … , Janine E. Oldham, Matthias G. von Herrath
Published May 26, 2009
Citation Information: J Clin Invest. 2009;119(6):1515-1523. https://doi.org/10.1172/JCI38503.
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Research Article

Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing β cells. Viral infections induce immune responses that can damage β cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on β cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death–1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8+ T cells expressing programmed cell death–1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4+CD25+ Tregs, which produced TGF-β and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4+CD25+ Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.

Authors

Christophe M. Filippi, Elizabeth A. Estes, Janine E. Oldham, Matthias G. von Herrath

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Figure 4

The frequency of natural CD4+CD25+ Tregs and their capacity to produce TGF-β are increased in the lymphoid organs of CVB3- and LCMV- immune NOD mice.

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The frequency of natural CD4+CD25+ Tregs and their capacity to produce T...
(A) Percentage of CD4+CD25+ T cells in the pancreatic LN and spleen of individual 12-week-old NOD mice left untreated or infected 21 days previously with CVB3 (orange triangles) or LCMV (green inverted triangles), as measured by flow cytometry. (B) Representative flow cytometry contour plots of Foxp3, CD127, CTLA-4, and glucocorticoid-induced tumor necrosis factor receptor (GITR) expression by CD4+CD25+ T cells in the pancreatic LN of individual 12-week-old NOD mice left untreated or infected 21 days previously with CVB3 or LCMV. Quadrants were defined based on isotype control stainings showing less than 0.2% positive cells for each parameter analyzed. Numbers indicate the percentage of cells in the corresponding quadrants. Comparable results were obtained in the spleen. (C) Representative flow cytometry contour plots of TGF-β, IL-10, IFN-γ, and TNF-α expression by CD4+CD25+ T cells from the pancreatic LN of individual 12-week-old NOD mice left untreated or infected 21 days previously with CVB3 or LCMV, as measured after PMA plus ionomycin stimulation. Quadrants were defined based on isotype control stainings showing less than 0.2% positive cells for each parameter analyzed. Numbers indicate the percentage of cells in the corresponding quadrants. Comparable results were obtained in the spleen. (D) Percentage of TGF-β–producing CD4+CD25+ T cells in the pancreatic LN and spleen of individual 12-week-old NOD mice left untreated or infected 21 days previously with CVB3 or LCMV, as measured by flow cytometry after PMA plus ionomycin stimulation. In A and D, symbols represent individual values, and horizontal lines denote mean. *P < 0.05, **P < 0.005, ***P < 0.001.