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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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.).
The authors declare no competing financial interests.
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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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