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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1480-1488
IMMUNOBIOLOGY
Regulation of interferon- gene expression by nuclear
factor of activated T cells
Alexander Kiani,
Francisco
J. García-Cózar,
Ivonne Habermann,
Stefanie Laforsch,
Toni Aebischer,
Gerhard Ehninger, and
Anjana Rao
From the Department of Pathology, Harvard Medical
School, and The Center for Blood Research, Boston, MA; the Department
of Medicine I, University Hospital Carl Gustav Carus, Dresden
University of Technology; and the Max-Planck-Institute for Infection
Biology, Berlin, Germany.
Transcription factors of the nuclear factor of activated T cells
(NFAT) family are thought to regulate the expression of a variety of
inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis
factor- . However, it remains unresolved whether NFAT proteins play a
role in regulating transcription of the interferon-  (IFN-) gene.
Here it is shown that the transcription factor NFAT1 (NFATc2) is a
major regulator of IFN- production in vivo. Compared with T cells
expressing NFAT1, T cells lacking NFAT1 display a substantial
IL-4-independent defect in expression of IFN- mRNA and protein.
Reduced IFN- production by NFAT1 /×
IL-4/ T cells is observed after primary in
vitro stimulation of naive CD4+ T cells, is conserved
through at least 2 rounds of T-helper cell differentiation, and occurs
by a cell-intrinsic mechanism that does not depend on overexpression of
the Th2-specific factors GATA-3 and c-Maf. Concomitantly,
NFAT1/× IL-4/ mice show increased
susceptibility to infection with the intracellular parasite
Leishmania major. Moreover, IFN- production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT,
VIVIT. These results suggest that IFN- production by T cells
is regulated by NFAT1, most likely at the level of gene transcription.
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