Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection.
Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. Here we show that IFN-alpha/beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha/beta induction of IFN-gamma. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.
Nguyen
Khuong B
KB
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
Watford
Wendy T
WT
Salomon
Rachelle
R
Hofmann
Sigrun R
SR
Pien
Gary C
GC
Morinobu
Akio
A
Gadina
Massimo
M
O'Shea
John J
JJ
Biron
Christine A
CA
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000276:immunology* / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000502:physiology; D008217:Lymphocytic choriomeningitis virus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D007370:Interferon Type I; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma