Target cell defense prevents the development of diabetes after viral infection.
The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic beta cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact beta cell response to IFNs was critical in preventing disease in infected hosts. The antiviral defense, raised by beta cells in response to IFNs, resulted in a reduced permissiveness to infection and subsequent natural killer (NK) cell-dependent death. These results show that beta cell defenses are critical for beta cell survival during CVB4 infection and suggest an important role for IFNs in preserving NK cell tolerance to beta cells during viral infection. Thus, alterations in target cell defenses can critically influence susceptibility to disease.
Flodström
Malin
M
Department of Immunology, IMM-23, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Maday
Amy
A
Balakrishna
Deepika
D
Cleary
Mary Malo
MM
Yoshimura
Akihiko
A
Sarvetnick
Nora
N
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000821:virology; D004351:Drug Resistance; D029822:Enterovirus B, Human / Q000276:immunology*; D004769:Enterovirus Infections / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000276:immunology* / Q000821:virology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000276:immunology; D014779:Virus Replication
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007371:Interferon-gamma