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Molecular and Cellular Biology, April 2001, p. 2716-2725, Vol. 21, No. 8
Department of Pathology and Center for
Immunology, Howard Hughes Medical Institute, Washington University
School of Medicine, St. Louis, Missouri 63110
Received 26 May 2000/Returned for modification 17 July
2000/Accepted 23 January 2001
Development of Th2 subset of CD4+ T cells involves the
interleukin-4 (IL-4)- and Stat6-dependent increase in GATA-3 expression during primary activation. Recently we reported that the phenotypic stability and factor independence of Th2 cells involves acquisition of
an intracellular pathway that maintains GATA-3 expression. Evidence
from retroviral expression studies implied that this pathway involved
an autoactivation of GATA-3 expression, since Stat6-deficient T cells
induced endogenous GATA-3 when infected with GATA-3-expressing
retroviruses. That study left unresolved the issue of whether GATA-3
autoactivation was direct or indirect. Several other Th2-specific
transcription factors have been described, including c-Maf and JunB. We
therefore examined the ability of these other transcription factors to
induce GATA-3 expression and promote Th2 development. Neither c-Maf nor
JunB induced Th2 development in Stat6-deficient CD4+ T
cells, in contrast to GATA-3. Consistent with this indication of a
possible direct autoactivation pathway, we also observed that
heterologous GATA family proteins GATA-1, GATA-2, and GATA-4 were also
capable of inducing GATA-3 expression in developing Stat6-deficient T
cells and promote Th2 development. Mutational analysis revealed
evidence for two distinct mechanisms of GATA-3 action. IL-4 induction
by GATA-3 required each of the functional domains to be present,
whereas repression of gamma interferon could occur even when mutants of
GATA-3 lacking the second transactivation domain, TA2, were expressed.
The GATA-dependent induction of the GATA-3 but not the other GATA genes
in T cells suggests that T-cell-specific cis elements
within the GATA-3 locus likely cooperate with a general GATA
recognition motif to allow GATA-3-dependent autoactivation.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2716-2725.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Structure and Specificity of GATA Proteins in Th2
Development
*
Corresponding author. Mailing address: Department of
Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 362-2009. Fax: (314) 747-4888. E-mail: murphy{at}immunology.wustl.edu.
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