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Autoimmune inflammation, such as in rheumatoid arthritis, is characterized by activated Th1 cells without sufficient Th2 differentiation that might downmodulate the chronic immune response. Delineation of the mechanisms that control T-cell differentiation is therefore of major importance for the understanding of the pathogenesis of autoimmune diseases. The transcription factor GATA-3 has been implicated in regulating Th2 cell differentiation in murine T cells in vitro, but its role in vivo and, in particular, in human T-cell differentiation is currently unknown. To dissect the role of GATA-3 in human T-cell differentiation and T-cell-mediated effector functions, we used the unique opportunity to analyze T-cell functions in human individuals lacking one functional GATA-3 allele. The patients had no history of severe or opportunistic infections, normal peripheral T-cell counts and normal frequencies and absolute numbers of CD4 helper and CD8 cytotoxic T cells. CD4 T cells from GATA-3+/- individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased Th2 frequencies in vivo, as determined by analyzing cytokine secretion profiles of freshly isolated CD4 T cells, and in vitro, as determined by employing an in vitro cell culture system that allows the differentiation of T-cell effectors after short-term priming. Moreover, Th2 cell-mediated effector functions, as assessed by serum levels of Th2-dependent immunoglobulins (IgG4, IgE), were dramatically decreased, whereas the Th1-dependent IgG1 was elevated compared with GATA-3+/+ controls. Concordant with these data, silencing of GATA-3 in GATA-3+/+ CD4 T cells with small interfering RNA significantly reduced Th2 cell differentiation. Moreover, GATA-3 mRNA levels increased under Th2-inducing conditions and decreased under Th1-inducing conditions in vitro. Taken together, the data strongly suggest that GATA-3 is an important transcription factor in regulating human Th2 cell differentiation in vivo. GATA-3 might therefore constitute a promising target for immunomodulatory treatment strategies in diseases that are characterized by biased activation of Th cell subsets, such as autoimmune diseases or allergies.