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Departments of Pathology and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093
The NFAT5/TonEBP transcription factor, a recently identified
rel/NF-
B family member, activates transcription of osmocompensatory
genes in response to extracellular hyperosmotic stress. However, the
function of NFAT5 under isosmotic conditions present in vivo remains
unknown. Here we demonstrate that NFAT5 is necessary for optimal T cell
development in vivo and allows for optimal cell growth ex vivo under
conditions associated with osmotic stress. Transgenic mice expressing
an inhibitory form of NFAT5 in developing and mature T cells exhibited
a 30% reduction in thymic cellularity evenly distributed among thymic
subsets, consistent with the uniform expression and nuclear
localization of NFAT5 in each subset. This was associated with a 25%
reduction in peripheral CD4+ T cells and a 50% reduction
in CD8+ T cells. While transgenic T cells exhibited no
impairment in cell growth or cytokine production under normal culture
conditions, impaired cell growth was observed under both hyperosmotic
conditions and isosmotic conditions associated with osmotic stress.
Transgenic thymocytes also demonstrated increased sensitivity to
osmotic stress. Consistent with this, the system A amino acid
transporter gene ATA2 exhibited NFAT5 dependence under hypertonic
conditions but not in response to amino acid deprivation. Expression of
the TNF-
gene, a putative NFAT5 target, was not altered in
transgenic T cells. These results not only demonstrate an
osmoprotective function for NFAT5 in primary cells but also show that
NFAT5 is necessary for optimal thymic development in vivo, suggesting
that developing thymocytes within the thymic microenvironment are
subject to an osmotic stress that is effectively countered by
NFAT5-dependent responses.
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