Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development.
Nuclear factor of activated T cells (NFAT) is a critical regulator of early gene transcription in response to TCR-mediated signals. Here, we show that mice lacking both NFATp and NFAT4 develop a profound lymphoproliferative disorder likely due to a lowered threshold for TCR signaling coupled with increased resistance to apoptosis secondary to defective FasL expression. NFAT mutant mice also have allergic blepharitis, interstitial pneumonitis, and a 10(3) to 10(4) fold increase in serum IgG1 and IgE levels, secondary to a dramatic and selective increase in Th2 cytokines. This phenotype may be ascribed to unopposed occupancy of the IL-4 promoter by NFATc. Our data demonstrate that lymphoid homeostasis and Th2 activation require a critical balance among NFAT family members.
Ranger
A M
AM
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115-6017, USA.
Oukka
M
M
Rengarajan
J
J
Glimcher
L H
LH
D000542:Alveolitis, Extrinsic Allergic / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D001762:Blepharitis / Q000276:immunology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D053222:Fas Ligand Protein; D006706:Homeostasis / Q000502:physiology*; D007136:Immunoglobulins / Q000096:biosynthesis; D017563:Lung Diseases, Interstitial / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors