T-Bet Expression and Failure of GATA-3 Cross-Regulation Lead to Default Production of IFN-γ by γδ T Cells

Abstract

γδ T cells predominantly produce IFN-γ upon activation. To determine the basis for default production of IFN-γ by γδ T cells, we analyzed the transcription factors T-box expressed in T cells (T-bet) and GATA-3. T-bet, absent in naive γδ cells, was induced upon TCR signaling, with IFN-γ production. T-bet also regulated IL-4 synthesis, as γδ cells isolated from T-bet-deficient mice displayed enhanced IL-4 levels with reduced IFN-γ production. Notably, T-bet expression after TCR signaling in γδ cells was not down-regulated by IL-4, in conjunction with a higher ratio of T-bet:GATA-3 expression than that found in CD4+ T cells. Indeed, overexpression of GATA-3 failed to inhibit IFN-γ secretion in γδ cells to the degree seen in CD4+ T cells. These results indicate that T-bet enhances IFN-γ secretion and suppresses IL-4 secretion in γδ cells, and that GATA-3 fails to counterbalance T-bet-mediated IFN-γ production, accounting for the default synthesis of IFN-γ by these T lymphocytes.