STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response.
Interferons (IFNs) are key regulators for both innate and adaptive immune responses. By screening ENU-mutagenized mice, we identified a pedigree- P117 which displayed impaired response to type I, but not type II, IFNs. Through inheritance test, genetic mapping and sequencing, we found a T to A point mutation in the 5' splice site of STAT2 intron 4-5, leading to cryptic splicing and frame shifting. As a result, the expression of STAT2 protein was greatly diminished in the mutant mice. Nonetheless, a trace amount of functional STAT2 protein was still detectable and was capable of inducing, though to a lesser extent, IFNalpha-downstream gene expressions, suggesting that P117 is a STAT2 hypomorphic mutant. The restoration of mouse or human STAT2 gene in P117 MEFs rescued the response to IFNalpha, suggesting that the mutation in STAT2 is most likely the cause of the phenotypes seen in the pedigree. Development of different subsets of lymphocytes appeared to be normal in the mutant mice except that the percentage and basal expression of CD86 in splenic pDC and cDC were reduced. In addition, in vitro Flt3L-dependent DC development and TLR ligand-mediated DC differentiation were also defective in mutant cells. These results suggest that STAT2 positively regulates DC development and differentiation. Interestingly, a severe impairment of antiviral state and increased susceptibility to EMCV infection were observed in the mutant MEFs and mice, respectively, suggesting that the remaining STAT2 is not sufficient to confer antiviral response. In sum, the new allele of STAT2 mutant reported here reveals a role of STAT2 for DC development and a threshold requirement for full functions of type I IFNs.
Chen
Lan-Sun
LS
Graduate Institute of Immunology, National Taiwan University College of Medicine, 1 Jen-Ai Road, Section 1, Rm 513, Taipei 100, Taiwan, Republic of China. lanson.chen@gmail.com
Wei
Pei-Chi
PC
Liu
Taming
T
Kao
Chung-Hsuan
CH
Pai
Li-Mei
LM
Lee
Chien-Kuo
CK
D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D055633:Immune System Phenomena / Q000502:physiology*; D016898:Interferon-alpha / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014780:Viruses / Q000378:metabolism* / Q000472:pathogenicity
D016898:Interferon-alpha; D050795:STAT2 Transcription Factor; D007371:Interferon-gamma