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Maximal and sustained activation of T lymphocytes requires integration of the signaling pathways downstream of the TCR (T Cell Receptor) and of coreceptors such as CD28.Upon T cell activation, TCR signals induce the nuclear localization of NFATc 1 proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases.Such a rapid nuclear export allows continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling.We have generated a Tetracycline-regulated conditional transgenic mouse whose T cells express an NFATc 1 variant (NFATc 1nuc) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites.NFATc1nuc T cells have constitutively nuclear NFATc 1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro.NFATc 1 nuc T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation.These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors.In addition, NFATc1nuc destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.The level of nuclear NFATc1 expression was only 1/7th of the total NFATc1 molecules of a wild type T cell, however, such a subtle increase of NFATc 1 nuclear occupancy caused a severe disease with multi-organ failure characterized with infiltration of immune cells, elevated auto antibodies, leading to early animal death.Suppression of the transgene expression by doxycycline suppressed and reversed the disease, indicating the stringent control of NFATc1 nuclear occupancy is critical to maintaining balanced immune response.I will also discuss our results on the roles ofNFATc 1 in the regulation of bone homeostasis using the same transgenic mouse model.