GATA-3 in human T helper cell type 2 development

Abstract

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.