The addition of IL-12p75 to naïve CD4+ T cells promotes their differentiation towards a TH1-type cytokine pattern. Dendritic cells stimulated by LPS generate IL-12p75, but only if the environment also contains IFN-γ. Thus, it appears that IFN-γ is needed to start the response that will result in further production of IFN-γ. We previously reported that paradoxically DCs produce IL-12p75 only after engaging primed, but not naïve T cells. This study examines the mechanism by which primed T cells trigger IL-12p75 secretion and asks whether this induction is also dependent on the presence of IFN-γ. Here, we show that, in contrast to LPS, primed T cells induce IL-12p75 in an IFN-γ-independent manner. Addition of rIFN-γ to cocultures of naïve T cells with DCs did not induce IL-12p75. Moreover, antigen-activated CD4+ T cells from wild type or IFN-γ-deficient mice both initiated IL-12p75 production from DCs. Surprisingly, we found that synergies between three T-cell-derived factors – CD40 Ligand, IL-4 and GM-CSF – were necessary and sufficient for IL-12p75 production. These results suggest that there are at least two distinct pathways for IL-12p75 production in vivo. Furthermore, the T-cell-dependent pathway of IL-12p75 production employs molecules that are not classically associated with a TH1-type response.