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,
Departments of
*
Immunology,
Cell Biology and Genetics, and
Pulmonary Medicine, Faculty of Medicine, Erasmus University Rotterdam, Rotterdam, The Netherlands; and
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
The transcription factor GATA-3 is essential for early T cell
development and differentiation of naive CD4+ T
cells into Th2 effector cells. To study the function of GATA-3 during T
cell-mediated immune responses in vivo, we investigated
CD2-GATA3-transgenic mice in which GATA-3
expression is driven by the CD2 locus control region.
Both in the CD4+ and the
CD8+ T cell population the proportion of cells
exhibiting a
CD44highCD45RBlowCD62Llow
Ag-experienced phenotype was increased. In
CD2-GATA3-transgenic mice, large fractions of peripheral
CD4+ T cells expressed the IL-1 receptor family
member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T
cell stimulation, the ability to produce IL-2 and IFN-
was
decreased. Moreover, CD4+ T cells manifested
rapid secretion of the Th2 cytokines IL-4, IL-5, and IL-10, reminiscent
of Th2 memory cells. In contrast to wild-type
CD4+ cells, which lost GATA-3 expression when
cultured under Th1-polarizing conditions,
CD2-GATA3-transgenic CD4+ cells
maintained expression of GATA-3 protein. Under Th1 conditions, cellular
proliferation of CD2-GATA3-transgenic
CD4+ cells was severely hampered, IFN-
production was decreased and Th2 cytokine production was increased.
Enforced GATA-3 expression inhibited Th1-mediated in vivo
responses, such as Ag-specific IgG2a production or a delayed-type
hypersensitivity response to keyhole limpet hemocyanin.
Collectively, these observations indicate that enforced
GATA-3 expression selectively inhibits Th1 differentiation
and induces Th2 differentiation. The increased functional capacity to
secrete Th2 cytokines, along with the increased expression of surface
markers for Ag-experienced Th2-committed cells, would argue for a role
of GATA-3 in Th2 memory formation.
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