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-gammaR (IFN-gamma R2). Hence, the IFN-gamma -producing subset of Th cells is unresponsive to IFN-gamma. Analysis of IFN-gamma producing CD8(+) T cells demonstrates that, like Th1 cells, these cells do not express IFN-gamma R2. To define the importance of IFN-gamma signaling for the development of functional CD8(+) T cells, mice either lacking IFN-gamma R2 or overexpressing this protein were examined. While CD8(+) T cell development and function appear normal in IFN-gamma R2(-/-) mice, CD8(+) T cell function in IFN-gamma R2 transgenic is altered. IFN-gamma R2 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-gamma in response to antigenic stimulation. Therefore, although IFN-gamma signaling is not required for the generation of normal cytotoxic T cells, constitutive IFN-gamma signaling can selectively impair the cytotoxic function of CD8(+) T cells.