Role of NFATx (NFAT4/NFATc3) in expression of immunoregulatory genes in murine peripheral CD4+ T cells.
Ca(2+)-regulated NFAT family members are transcription factors crucial for the expression of various cytokine genes and other immunoregulatory genes. Analyses of mice defective in one or two NFAT family members have revealed functions specific to each NFAT gene. However, the redundant functions of several family members limit the usefulness of gene disruption analysis. For example, CD4(+) T cells isolated from NFATx-disrupted mice do not show any modulation in cytokine gene expression, perhaps because other family members compensate for its absence. To analyze the role of NFATx in the regulation of immunoregulatory genes in T cells, we made a gain-of-function mutant by creating transgenic mice expressing a constitutively nuclear form of NFATx in T cell lineages. In naive CD4(+) T cells, NFATx up-regulated the expression of several cytokine genes and activation markers and suppressed the expression of CD154. In Th1 cells, NFATx enhanced the expression of the Th1 cytokine genes, IFN-gamma and TNF-alpha. In contrast, NFATx suppressed Th2 cytokine genes such as IL-4 and IL-5 in Th2 cells. It has been reported that both NFAT1 and NFATx are required to maintain the homeostasis of the immune system. Our results suggest that NFATx exerts this function by inhibiting the expression of some critical immunoregulatory genes.
Chen
Jingtao
J
Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Amasaki
Yoshiharu
Y
Kamogawa
Yumiko
Y
Nagoya
Miho
M
Arai
Naoko
N
Arai
Ken-ichi
K
Miyatake
Shoichiro
S
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D019041:L-Selectin / Q000096:biosynthesis; D037181:Lectins, C-Type; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010957:Plasmids; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D019076:Transgenes / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D019041:L-Selectin; D037181:Lectins, C-Type; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D000099192:CD69 Antigens; C494009:Nfatc3 protein, mouse