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RNA regulator NF90 is essential for T‐cell homeostasis and normal IL‐2 expression
Author(s) -
Kao Peter N.,
Shi Lingfang,
Godfrey Wayne R.,
Lin Joseph
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a931-c
Subject(s) - microbiology and biotechnology , biology , t cell , il 2 receptor , ionomycin , gene expression , gene , immune system , immunology , biochemistry , intracellular
T‐cell expression of IL‐2 is regulated at the levels of transcription, posttranscriptional mRNA stabilization and translation. NF90 is a double‐stranded RNA‐binding protein subunit of a native nuclear complex that binds to the nuclear factor of activated T‐cells (NF‐AT) target DNA sequence in the IL‐2 promoter. NF90 binding to AU‐rich elements (ARE) in the 3′ untranslated region (UTR) stabilizes IL‐2 mRNA and facilitates nuclear export. Mice with targeted disruption of NF90 die after birth due to defective terminal differentiation of skeletal muscles and respiratory failure. The molecular mechanisms involve NF90 binding to the AREs in the 3′ UTRs of MyoD, myogenin and p21Cip1/Waf1 mRNAs, conferring stability and translational expression (Shi, Zhao, Qiu, Godfrey, Vogel, Rando, Hu and Kao, J Biol Chem 280:18981–18989, 2005). To characterize the contributions of NF90 to immune development and T‐cell function, fetal liver cells from NF90 gene‐targeted mice were transplanted into irradiated recombination activating gene (RAG)‐2(−/−) and IL2R (−/−) adult mice that lack T‐, B‐ and NK cells. Compared to NF90(+/+) and NF90(+/−) donors, NF90(−/−)‐RAG reconstituted mice demonstrated decreased numbers of CD4+ and CD8+ T‐cells in peripheral blood. NF90(−/−)‐RAG thymic, splenic and purified splenic CD4+ T‐cells demonstrated profound decreases in IL‐2 secretion following primary stimulations with phorbol myristyl acetate + ionomycin, concanavalin A or anti‐CD3 + CD28. Deficiency of NF90 is associated with T‐cell lymphocytopenia in vivo and impaired IL‐2 secretion in vitro in reconstituted T‐cells. Supported by NIH R01AI39624.