A role of calcineurin in coreceptor regulation during differentiation of Cd4+Cd8+ T cells.
The immunosuppressant FK506 inhibits thymocyte positive selection. Calcineurin, a FK506-sensitive Ca2+/calmodulin-dependent protein phosphatase, is presumed to be involved in this event without direct evidence. We have previously shown that moderate stimulation of CD4(+)CD8(+) thymocytes with a combination of the calcium ionophore ionomycin and phorbol myristate acetate mimics positive selection events including downregulation of CD8 expression. Moderate stimulation of a CD4(+)CD8(+) T cell line with the same combination of drugs also induced specific downregulation of CD8 expression. FK506 inhibited the CD8 downregulation in both cell types. The T cell line was transfected with an expression vector encoding an active form of calcineurin. The transfectans remained CD4(+)CD8(+), but became CD4(+)CD8(-) or CD4(+)CD8(low) upon stimulation with phorbol myristate acetate alone. The extent of the CD8 downregulation was correlated with the expression level of the mutant calcineurin. These results suggest that the calcium signal for the CD8 downregulation is mainly delivered through calcineurin activation.
Kuwata
T
T
Integrative Projects, Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Asada
A
A
Ohoka
Y
Y
Mukai
M
M
Miyaike
M
M
Iwata
M
M
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D015704:CD4 Antigens; D016827:CD8 Antigens; D007166:Immunosuppressive Agents; D007476:Ionophores; D012333:RNA, Messenger; D015759:Ionomycin; D019703:Calcineurin; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus