NF90 regulates inducible IL-2 gene expression in T cells.
Activation of T cells induces the production of T cell growth and survival factor interleukin (IL) 2. Regulatory T cells intrinsically fail to induce IL-2 expression upon activation and can suppress IL-2 production in conventional T cells. Thus, the control of IL-2 expression is critically important to T cell immune responses, yet the mechanisms remain incompletely understood. Nuclear factor (NF) 90 is a zinc-finger DNA- and double-stranded RNA-binding protein subunit that binds specifically to the antigen receptor response element (ARRE)/NF of activated T cells target sequence in the IL-2 proximal promoter. Inducible binding of NF90 to the IL-2 promoter in vivo is shown by chromatin immunoprecipitation. NF90 gene-targeted mice exhibit perinatal lethality. Compared with newborn NF90(+/+) mice, newborn NF90(-/-) mice demonstrate severe impairment of IL-2 expression. Compared with wild-type cells, T cells deficient in NF90 are impaired in ARRE and IL-2 transcriptional activation and IL-2 mRNA stabilization. Fetal liver cells from NF90 gene-targeted mice were transplanted into irradiated adult recombination activating gene (RAG)-2(-/-) and IL-2Rgamma(-/-) mice deficient in T cells, B cells, and natural killer cells. NF90(+/+)- and NF90(-/-)-RAG chimeric mice showed grossly normal repopulation of the thymus and spleen, but only NF90(-/-) T cells were severely impaired in IL-2 gene expression. Compared with littermates, NF90(-/-) RAG chimeric mice exhibited profound T cell lymphocytopenia in the peripheral circulation. Thus, NF90 regulates inducible IL-2 transcription, mRNA stability, and gene expression in T cells and represents a novel therapeutic target for the modulation of T cell immune responses.
Shi
Lingfang
L
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, CA 94305, USA.
Godfrey
Wayne R
WR
Lin
Joseph
J
Zhao
Guohua
G
Kao
Peter N
PN
D000818:Animals; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050779:Nuclear Factor 90 Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050779:Nuclear Factor 90 Proteins; C499308:Rag2 protein, mouse; D008156:Luciferases