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,
,
*
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany; and Departments of
Respiratory Diseases Research and
Transplantation Research, Novartis Pharma, Inc., Basel, Switzerland
We have shown previously that human
CD4+45RO- T cells could be primed for a
Th2 phenotype independent of IL-4 if they were activated by
anti-CD28 mAb plus IL-2. If additional TCR signals were provided,
the cells differentiated toward Th1 independent of IL-12. Here we show
that anti-CD28/IL-2-primed Th2 cells expressed high levels of
activated STAT6, but no cytokine mRNA. Moreover, both Th1 and Th2 cells
expressed active STAT1 and -3, but not STAT2, -4, and -5. Restimulation
of Th1 or Th2 cells via CD3 plus CD28 induced production of IFN-
or
IL-4, respectively, but did not alter the activation status/DNA binding
activity of STATs. Addition of IL-4 (or anti-IL-4 mAb) to
restimulated Th2 cells did not modulate STAT6 activation or IL-4
expression, confirming the full commitment. However, Th2 cells remained
responsive to IL-12, which repressed STAT6 DNA binding but activated
STAT4, and this coincided with a suppression of IL-4/IL-5 and an
induction of IFN-. In Th1 cells, IL-12 activated both STAT6 and
STAT4, and IL-4 activated STAT6, but in both cases the Th1 phenotype
remained. Together the data show that CD28/IL-2-dependent Th2 priming
activated STAT6 without inducing IL-4 expression. The primed Th cells
resembled memory cells and produced IL-4 upon the first CD3/CD28
costimulus without detectable modulation of STATs. Th2 cells remained
responsive to IL-12, which repressed STAT6 DNA binding and activated
STAT4, and switched the cells to Th1. The effects of IL-12 may depend
on the commitment of the cells, since IL-12 phosphorylated STAT6 in Th1
and dephosphorylated STAT6 in Th2 cells.
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