High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells.
The best-characterized type 1 interferon (IFN) signaling pathway depends on signal transducer and activator of transcription 1 (STAT1) and STAT2. The cytokines can, however, conditionally activate all STATs. Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-gamma induction, and NK cells are major producers of this cytokine. We report that NK cells have high basal STAT4 levels and sensitivity to type 1 IFN-mediated STAT4 activation for IFN-gamma production. Increases in STAT1, driven during viral infection by either type 1 IFN or IFN-gamma, are associated with decreased STAT4 access. Both STAT1 and STAT2 are important for antiviral defense, but STAT1 has a unique role in protecting against sustained NK cell IFN-gamma production and resulting disease. The regulation occurs with an NK cell type 1 IFN receptor switch from a STAT4 to a STAT1 association. Thus, a fundamental characteristic of NK cells is high STAT4 bound to the type 1 IFN receptor. The conditions of infection result in STAT1 induction with displacement of STAT4. These studies elucidate the critical role of STAT4 levels in predisposing selection of specific signaling pathways, define the biological importance of regulation within particular cell lineages, and provide mechanistic insights for how this is accomplished in vivo.
Miyagi
Takuya
T
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Gil
M Pilar
MP
Wang
Xin
X
Louten
Jennifer
J
Chu
Wen-Ming
WM
Biron
Christine A
CA
D000818:Animals; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050797:STAT4 Transcription Factor; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma