Regulation of IFN-γ signaling is essential for the cytotoxic activity of CD8⁺ T cells

Previous studies have demonstrated that, as naive murine CD4⁺ cells differentiate into Th1 cells, they lose expression of the second chain of IFN-γR (IFN-γR2). Hence, the IFN-γ-producing subset of Th cells is unresponsive to IFN-γ. Analysis of IFN-γ-producing CD8⁺ T cells demonstrates that, like Th1 cells, these cells do not express IFN-γR2. To define the importance of IFN-γ signaling for the development of functional CD8⁺ T cells, mice either lacking IFN-γR2 or overexpressing this protein were examined. While CD8⁺ T cell development and function appear normal in IFN-γR2^-/- mice, CD8⁺ T cell function in IFN-γR2 transgenic is altered. IFN-γR2 transgenic CD8⁺ T cells are unable to lyse target cells in vitro. However, these cells produce Fas ligand, perforin, and granzyme B, the effector molecules required for killing. Interestingly, TG CD8⁺ T cells proliferate normally and produce cytokines, such as IFN-γ in response to antigenic stimulation. Therefore, although IFN-γ signaling is not required for the generation of normal cytotoxic T cells, constitutive IFN-γ signaling can selectively impair the cytotoxic function of CD8⁺ T cells.