Regulation of IFN-gamma signaling is essential for the cytotoxic activity of CD8(+) T cells

Previous studies have demonstrated that, as naive murine CD4(+) cells diffe rentiate into Th1 cells, they lose expression of the second chain of IFN-ga mmaR (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 d emonstrates that, like Th1 cells, these cells do not express IFN-gamma R2. To define the importance of IFN-gamma signaling for the development of func tional CD8(+) T cells, mice either lacking IFN-gamma R2 or overexpressing t his protein were examined. While CD8(+) T cell development and function app ear normal in IFN-gamma R2(-/-) mice, CD8(+) T cell function in IFN-gamma R 2 transgenic is altered. IFN-gamma R2 transgenic CD8(+) T cells are unable to lyse target cells in vitro. However, these cells produce Fas ligand, per forin, and granzyme B, the effector molecules required for killing. Interes tingly, 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 ce lls, constitutive IFN-gamma signaling can selectively impair the cytotoxic function of CD8(+) T cells.