Dominance of IL-12 over IL-4 in γδ T cell differentiation leads to default production of IFN-γ:: Failure to down-regulate IL-12 receptor β2-chain expression

gamma delta T cells secrete Th1- and Th2-like cytokines that help mediate innate and acquired immunity, We have addressed the mechanism whereby murine gamma delta T cells acquire the capacity to differentially produce such cytokines. Splenic gamma delta T cells could be polarized into IFN-gamma- or IL-4-secreting cells in vitro; however, in contrast to CD4(+) alpha beta T cells, gamma delta T cells predominantly produced IFN-gamma, even in the presence of IL-4, a finding independent of genetic background. Like CD4(+) Th cells, IFN-gamma-producing cells expressed the IL-12 receptor beta(2)-chain after activation in the presence of IL-12; however, unlike Th2 cells, IL-4-primed gamma delta T cells also expressed this receptor, even in the absence of IFN-gamma and despite the presence of the transcription factor GATA-3. IL-12 also induced IL-4-primed gamma delta T cells to proliferate and to translocate Stat3/Stat4, indicating signaling through the IL-12 receptor. These molecular events can account for the predominant production of IFN-gamma by gamma delta T cells in the presence of IL-12, despite the availability of IL-4. Early and predominant production of IFN-gamma by gamma delta T cells likely is critical for the roles that these cells play in protection against intracellular pathogens and in tumor immunity.