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*
Center for Blood Research, Harvard Medical School, Boston, MA 02115;
Division of Rheumatology and Clinical Immunology, Department of Medicine, Albert Ludwigs University, Freiburg, Germany; and
Max Planck Institute for Immunobiology, Freiburg, Germany
The expression of cytokine genes and other inducible genes is
crucially dependent on the pattern and duration of signal transduction
events that activate transcription factor binding to DNA. Two infant
patients with SCID and a severe defect in T cell activation displayed
an aberrant regulation of the transcription factor NFAT. Whereas the
expression levels of the NFAT family members NFAT1, -2, and -4 were
normal in the patients’ T cells, dephosphorylation and nuclear
translocation of these NFAT proteins occurred very transiently and
incompletely upon stimulation. Only after inhibition of nuclear export
with leptomycin B were we able to demonstrate a modest degree of
nuclear translocation in the patients’ T cells. This transient
activation of NFAT was not sufficient to induce the expression of
several cytokines, including IL-2, IL-3, IL-4, and IFN-
, whereas
mRNA levels for macrophage inflammatory protein-1
, GM-CSF, and IL-13
were only moderately reduced. By limiting the time of NFAT activation
in normal control cells using the calcineurin inhibitor cyclosporin A,
we were able to mimic the cytokine expression pattern in SCID T cells,
suggesting that the expression of different cytokine genes is
differentially regulated by the duration of NFAT residence in the
nucleus.
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