Negative Regulation of CD8+ T Cell Function by the IFN-Induced and Double-Stranded RNA-Activated Kinase PKR

Abstract

The IFN-induced and dsRNA-activated kinase (PKR) mediates the antiviral and antiproliferative effects of IFN-alpha and IFN-gamma. Despite these findings, PKR:(-/-) mice have no overt immunological phenotype. Here we tested the role of PKR in cellular immunity by determining the induction and elicitation of contact hypersensitivity in PKR:(-/-) mice, a model of T cell-mediated immunity. When compared with wild type, the magnitude of contact hypersensitivity responses in PKR:(-/-) mice were 2-fold higher and of extended duration. This was also observed when naive recipients of immune CD8(+) T cells from sensitized PKR:(-/-) and CD4(+) T cells from sensitized wild-type PKR:(+/+) or PKR:(-/-) mice were challenged with hapten, indicating a regulatory defect intrinsic to the CD8(+) T cell population. Isolated lymph node T cells from PKR:(-/-) mice were hyperproliferative during Con A-mediated stimulation. These results implicate PKR for the first time in the growth control of mature T lymphocytes and give insight into the negative regulation of CD8(+) T cell-mediated immune responses.