Negative regulation of CD8+ T cell function by the IFN-induced and double-stranded RNA-activated kinase PKR.
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.
Kadereit
S
S
Departments of. Cancer Biology and Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Xu
H
H
Engeman
T M
TM
Yang
Y L
YL
Fairchild
R L
RL
Williams
B R
BR
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000637:transplantation; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis
D019014:fas Receptor; D015847:Interleukin-4; D007371:Interferon-gamma; D019892:eIF-2 Kinase