IFN-γ mediates the death of Th1 cells in a paracrine manner

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