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

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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 3

LCMV-induced upregulation of PD-L1 in prediabetic NOD mice prevents the expansion of IGRP-specific CD8+ T cells and delays the onset of T1D.

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LCMV-induced upregulation of PD-L1 in prediabetic NOD mice prevents the ...
(A) Different siRNAs specific for PD-L1 were assessed for efficacy by infection of NOD splenocytes for 24 hours with LCMV in vitro (MOI, 1) after transfection with different siRNAs (in duplicate). Shown is inhibition of PD-L1 upregulation, calculated as the percentage of PD-L1hi cells in populations infected with LCMV and transfected with siRNA relative to the percentage of PD-L1hi cells in the population infected with LCMV and transfected with scrambled-sequence siRNA, ± SD for duplicate samples. (B) Percentage of PD-L1hi cells over time in the pancreatic LN and spleen of individual NOD mice infected at 9 weeks of age with LCMV and simultaneously injected with cationic vehicle alone or containing 150 μg PD-L1 siRNA 76238, as measured by flow cytometry. (C) Percentage of IGRP-specific CD8+ T cells in the pancreatic LN and spleen of individual 12-week-old NOD mice injected 21 days previously with cationic vehicle alone and left untreated or simultaneously infected with LCMV (green inverted triangles) or injected 21 days previously with cationic vehicle containing PD-L1 siRNA 76238 and simultaneously infected with LCMV (white inverted triangles), as measured by flow cytometry after staining with NRP-V7 tetramer. In B and C, symbols represent individual values, and horizontal lines denote mean. (D) Cumulative diabetes incidence over time in NOD mice injected at 9 weeks of age with cationic vehicle alone and left untreated or simultaneously infected with LCMV or injected 21 days previously with cationic vehicle containing PD-L1 siRNA 76238 and simultaneously infected with LCMV. *P < 0.05, **P < 0.005, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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