Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.
Signal transducers and activators of transcription (STATs) are activated by tyrosine phosphorylation in response to cytokines and mediate many of their functional responses. Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6,7). IL-12 is required for the T-cell-independent induction of the cytokine interferon (IFN)-gamma, a key step in the initial suppression of bacterial and parasitic infections. IL-12 is also important for the development of a Th1 response, which is critical for effective host defence against intracellular pathogens. To determine the function of Stat4 and its role in IL-12 signalling, we have produced mice that lack Stat4 by gene targeting. The mice were viable and fertile, with no detectable defects in haematopoiesis. However, all IL-12 functions tested were disrupted, including the induction of IFN-gamma, mitogenesis, enhancement of natural killer cytolytic function and Th1 differentiation.
Thierfelder
W E
WE
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
van Deursen
J M
JM
Yamamoto
K
K
Tripp
R A
RA
Sarawar
S R
SR
Carson
R T
RT
Sangster
M Y
MY
Vignali
D A
DA
Doherty
P C
PC
Grosveld
G C
GC
Ihle
J N
JN
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018390:Gene Targeting; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013091:Spermatogenesis / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma