Th1 cells have different capacities to develop into memory cells based on their production of IFN-gamma. In this study, the mechanism by which a homogenous population of IFN-gamma-producing CD4 T cells was eliminated in vivo was assessed. When such cells were transferred into naive mice and activated with Ag, a striking decrease in the frequency of cells in the spleen and lung was observed. However, administration of neutralizing anti-IFN-gamma Ab at the time of Ag challenge largely prevented the elimination of such cells. To determine whether IFN-gamma was mediating its effects directly and/or indirectly, the ability of IFN-gamma to effectively signal in such cells was assessed in vitro. Indeed, there was reduced phosphorylation of STAT1 in response to IFN-gamma as well as markedly reduced expression of the IFN-gammaR beta-chain. Furthermore, transfer of such cells into IFN-gammaR-deficient mice limited their death following activation with Ag. Together, these data suggest that IFN-gamma acts in a paracrine manner to mediate the death of activated IFN-gamma-producing Th1 cells. In contrast to Ag stimulation, administration of CpG alone resulted in the elimination of Th1 cells in IFN-gammaR-/- mice. These results show that in response to Ag stimulation, the death of IFN-gamma-producing effector Th1 cells is controlled in an IFN-gamma-dependent manner, whereas in response to innate activation, the death of IFN-gamma-producing Th1 cells can occur through an IFN-gamma-independent pathway. Collectively, these data show the multiple mechanisms by which Th1 effector cells are efficiently eliminated in vivo.