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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2075-2083
IMMUNOBIOLOGY
Inhibitory effect on natural killer activity of microphthalmia
transcription factor encoded by the mutant mi allele
of mice
Akihiko Ito,
Tatsuki R. Kataoka,
Dae-Ki Kim,
Yu-ichiro Koma,
Young-Mi Lee, and
Yukihiko Kitamura
From the Department of Pathology, Osaka University
Medical School, Suita, Osaka, Japan.
The mouse mi locus encodes a
basic-helix-loop-helix-leucine zipper-type transcription factor,
microphthalmia transcription factor (MITF). Mice of mi/mi
genotype express a mutant form of MITF (mi-MITF), whereas
mice of tg/tg genotype have a transgene in the 5' flanking
region of the mi gene and do not express MITF. Although the
mi/mi mouse is deficient in natural killer (NK) activity, it was found that the tg/tg mouse was normal in this
respect. To know the cause, spleen cells of both genotypes were
compared. Although the proportion of spleen cells expressing an NK cell marker, NK1.1, was comparable in both mice, the proportion of large
granular lymphocytes decreased only in mi/mi mice. The
difference between mi/mi and tg/tg mice was
reproducible in the culture supplemented with interleukin-2. Moreover,
the perforin gene expression was reduced in mi/mi-cultured
spleen cells. Wild-type (+) MITF transactivated, but
mi-MITF suppressed, the perforin gene promoter through the NF-P motif, a strong cis-acting element. However, neither
+-MITF nor mi-MITF bound the NF-P motif. Instead, 2 nuclear
factors that bound the NF-P motif were retained in the cytoplasm of
mi/mi-cultured spleen cells. In addition, overexpression
of mi-MITF resulted in cytoplasmic retention of the 2 NF-P
motif-binding factors in cytotoxic T lymphocytes. The presence of
mi-MITF rather than the absence of +-MITF appeared to lead
to poor transactivation of the NF-P motif by intercepting NF-P
motif-binding factors. This inhibitory effect of mi-MITF
may cause the deficient cytotoxicity of NK cells in mi/mi mice.
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