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GATA-3, a C2C2-type zinc finger transcription factor, regulates many steps of T cell development and differentiation. It is also required for optimal production of type 2 cytokines by CD8+ T cells. However, its role in the development and function of this subset of T cells is still poorly characterized. In this paper, we report that GATA-3 is required for MHC-mediated positive selection and final maturation of CD8 single-positive thymocytes. Deficiency of GATA-3 mediated by a CD4cre transgene led to age-dependent lymphadenopathy partly because of abnormal expansion of CD8+ T cells driven by a cell-extrinsic mechanism. Paradoxically, GATA-3-deficient CD8+ T cells were hyporesponsive to Ag stimulation due to a defect in the maintenance/ progression, but not initiation, of activation signals. More importantly, GATA-3-deficient CD8+ T cells were less efficient in killing Ag-bearing tumor cells in vivo. Taken together, our data further expand the role of GATA-3 in T cells. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Thl7, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-&kgr;B and its subsequent recruitment onto the I&kgr;B&agr; promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy. [ABSTRACT FROM AUTHOR]