- 作者: Lan-Sun Chen; Pei-Chi Wei; Taming Liu; Chung-Hsuan Kao; Li-Mei Pai; Chien-Kuo Lee
- 作者服務機構: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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, IFNα-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 IFNα, 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. - 中文關鍵字: --
- 英文關鍵字: --