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 5

CD4+CD25+ Tregs modulated during the prediabetic phase by CVB3 or LCMV infection in vivo are capable of diminishing T1D incidence in NOD mice through TGF-β production.

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CD4+CD25+ Tregs modulated during the prediabetic phase by CVB3 or LCMV i...
(A) Cumulative diabetes incidence over time in NOD mice left untreated (None) or injected at 12 weeks of age with 5 × 105 CD4+CD25+ T cells purified from 12-week-old NOD donors left untreated (Naive Tregs) or infected 21 days previously with CVB3 (CVB3 Tregs) or LCMV (LCMV Tregs). CD4+CD25– T cells from CVB3- or LCMV-immune mice had no effect on disease outcome (data not shown). (B) The efficacy of transfection in CD4+CD25+ T cells was assessed by measuring by flow cytometry GFP and TGF-β expression in naive Tregs (purified as described in A) 15 hours after transfection with an empty plasmid (Control plasmid, top) or plasmid containing a cDNA (Encoding plasmid, bottom) encoding GFP (left) or TGF-β1 (right, assessed after PMA plus ionomycin stimulation). Shown are flow cytometry contour plots representative of 2 samples per group. Numbers indicate the percentage of cells in the corresponding gate/quadrant. (C) Cumulative diabetes incidence over time in NOD mice left untreated (None) or injected at 12 weeks of age with 5 × 105 naive Tregs transfected with an empty plasmid (Naive ctrl Tregs) or plasmid containing a cDNA encoding human TGF-β1 (Naive TGF-β Tregs). *P < 0.05, **P < 0.005.