Retarded thymic involution and massive germinal center formation in NF-ATp-deficient mice.
NF-ATp and NF-ATc are the most prominent nuclear NF-AT transcription factors in peripheral T lymphocytes. After T cell activation both factors bind to and control the promoters and enhancers of numerous lymphokine and receptor ligand genes. In order to define a specific role for NF-ATp in vivo we have inactivated the NF-ATp gene by gene targeting in mice. We show that NF-ATp deficiency leads to the accumulation of peripheral T cells with a "preactivated" phenotype, enhanced immune responses of T cells after secondary stimulation in vitro and severe defects in the proper termination of antigen responses, as shown by a reduced deletion of superantigen-reactive CD4+ T cells. These alterations in the function of the immune system are correlated with drastic changes in the morphology of lymphoid organs. Approximately 25 % of NF-ATp-deficient mice older than 6 months develop large germinal centers in the spleen and peripheral lymph nodes. In addition, they exhibit a pronounced retardation in the involution of the thymus. The thymus of these NF-ATp-deficient mice exhibits large cortical areas typical for newborn mice and a massive infiltration of IgM+/ IgD+ B lymphocytes. Contrary to the T lymphocytes from IL-2-deficient mice which develop a phenotype similar to the NF-ATp-/- mice, NF-ATp-/- T cells do not show obvious defects in Fas-mediated apoptosis. This might indicate defects in other types of programmed cell death which are controlled by the activity of NF-ATp.
Institute of Pathology, University of Würzburg, Germany.
K
K
Schuh
B
B
Kneitz
J
J
Heyer
U
U
Bommhardt
E
E
Jankevics
F
F
Berberich-Siebelt
K
K
Pfeffer
H K
HK
Müller-Hermelink
A
A
Schimpl
E
E
Serfling
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018089:Superantigens; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D019014:fas Receptor
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018089:Superantigens; D014157:Transcription Factors; D019014:fas Receptor