Target cell defense prevents the development of diabetes after viral infection

Abstract

The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic β cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact β cell response to IFNs was critical in preventing disease in infected hosts. The antiviral defense, raised by β cells in response to IFNs, resulted in a reduced permissiveness to infection and subsequent natural killer (NK) cell–dependent death. These results show that β cell defenses are critical for β cell survival during CVB4 infection and suggest an important role for IFNs in preserving NK cell tolerance to β cells during viral infection. Thus, alterations in target cell defenses can critically influence susceptibility to disease.

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Figure 1: STAT1 is phosphorylated in insulin-producing cells after stimulation with IFNs.
Figure 2: SOCS-1 is expressed in pancreatic islets from SOCS-1–Tg NOD mice, but is absent in islets from non-Tg littermates.
Figure 3: An intact β cell response to IFNs is critical for the inhibition of CVB4 replication in vitro.
Figure 4: Acute onset of diabetes in SOCS-1–Tg NOD and NOD-SCID mice infected with CVB4.
Figure 5: Insulin-staining β cells are lost in SOCS-I–Tg NOD mice infected with CVB4.
Figure 6: The tropism of CVB4 for islet cells is altered when IFN signaling is perturbed.
Figure 7: CVB4 and insulin colocalize in the pancreatic islet cells of infected SOCS-1–Tg NOD mice.
Figure 8: Adaptive immunity is not necessary for the swift induction of diabetes in CVB4-infected SOCS-1–Tg NOD mice, but depletion of NK cells prevents diabetes development.
Figure 9: Depletion of NK cells prevents the loss of insulin-staining β cells after CVB4 infection of SOCS-1–Tg NOD mice.

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Acknowledgements

We thank L. Mocknic, A. Ilic and L. Tucker for excellent technical assistance; N. Hill, M. Horwitz, C. King, M. Kritzik, S. Pakala, F. Shi and other members of the Sarvetnick laboratory for discussions and suggestions; P. Minick for editing the manuscript; and B. Smith and M. Wood (Core Electron Microscope Facility, The Scripps Research Institute) for assistance with electron and confocal microscopy. Supported by National Institutes of Health grants (ROI: AI42231), the National Multiple Sclerosis Society (M. F.) and the Juvenile Diabetes Research Foundation (M. F.).

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Correspondence to Nora Sarvetnick.

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Flodström, M., Maday, A., Balakrishna, D. et al. Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 3, 373–382 (2002). https://doi.org/10.1038/ni771

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