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Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611
T cell activation is known to be critically regulated by the extent
and duration of TCR-induced signaling pathways. The NFAT family of
transcription factors is believed to play an important role in coupling
these quantitative differences in TCR-induced signaling events into
changes in gene expression. In this study we have specifically
investigated the effects of sustained NFAT signaling on T cell
activation by introducing a constitutively active mutant version of
NFATc1 (caNFATc1) into primary murine CD4+ T cells and
examining its effects on gene expression. We now report that ectopic
expression of caNFATc1 partially mimics TCR signaling, resulting in
enhanced expression of CD25 and CD40 ligand and down-regulation of
CD62L. More importantly, we find that expression of caNFATc1 in T cells
maintained under either nonpolarizing or Th1-skewing conditions leads
to a marked selective increase in the number of cells expressing the
prototypical Th1 cytokine, IFN-
. Furthermore, when expressed in
Th2-skewed cells, caNFATc1 appears to attenuate Th2 differentiation by
decreasing production of IL-4 and promoting the expression of IFN-.
Finally, we find that caNFATc1 enhances expression of functional
P-selectin glycoprotein ligand-1, up-regulates Fas ligand expression,
and increases susceptibility to activation-induced cell death, cellular
traits that are preferentially associated with Th1 effector cells.
Taken together, these results suggest that sustained NFAT signaling,
mediated by ectopic expression of caNFATc1, acts to promote a Th1-like
pattern of gene expression and thereby serves to highlight the
important relationship between the degree of NFAT signaling and the
qualitative pattern of gene expression induced during T cell
activation.
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