Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice.
NF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L and FasL. A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo. The transcription of other cytokines including IL-13, GM-CSF, and TNF alpha was also affected, though to a lesser degree. Interestingly, the cytokines IL-2 and IFN gamma were minimally affected. Despite this early defect in IL-4 transcription, Th2 development was actually enhanced at later timepoints as evidenced by increased IL-4 production and IgE levels in situations that favor the formation of Th2 cells both in vitro and in vivo. These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response.
Hodge
M R
MR
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Ranger
A M
AM
Charles de la Brousse
F
F
Hoey
T
T
Grusby
M J
MJ
Glimcher
L H
LH
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D023201:CD40 Ligand; D002455:Cell Division; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D015870:Gene Expression; D018390:Gene Targeting; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D023201:CD40 Ligand; D015847:Interleukin-4