Effect of staphylococcal enterotoxin B-induced anergy on cytokine gene expression: anergy-sensitive and resistant mRNA expression.
We examined the effect of staphylococccal enterotoxin B (SEB)-induced anergy on expression of six different cytokine genes in T cells restimulated with SEB in vitro. We found that although IL-2, IL-3, and IL-4 mRNA levels are substantially reduced in anergic T cells, mRNAs for IL-6, IL-10, IFN-gamma, and TNF-alpha are expressed normally. Thus, there appeared both anergy-sensitive and resistant cytokine mRNA expression in restimulated anergic T cells. The same pattern of cytokine mRNA responses was observed in anergic CD4+ T cells, indicating that the preferential induction of anergy in Th1-like cells is not evident in this in vivo model. Employing TCR V beta 8.2 transgenic mice in which almost all T cells become anergic, we found that the TCR/CD3 complex can transduce both anergy-sensitive and resistant signals. Furthermore, a series of experiments using FK506, A23187, and PMA suggests that signals between TCR and activation of calcineurin and protein kinase C may be blocked in anergic T cells. This is supported by our gel mobility shift assays indicating that calcineurin and/or PMA-inducible NF-ATp, OAP40, and AP-1, but not calcineurin-independent Oct-2, are repressed in anergic spleen T cells upon restimulation with SEB. Taken together, these results suggest that, among signals elicited by stimulation of TCR with SEB, a Ca2+/calcineurin-NF-ATp pathway and other signals, including protein kinase C, are repressed in anergic T cells upstream of their activation, which are essential for the cytokine mRNA expression of the anergy-sensitive type but are dispensible for those of the anergy-resistant type.
Koide
Y
Y
Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Japan.
Uchijima
M
M
Yoshida
A
A
Yoshida
T O
TO
D000818:Animals; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D000001:Calcimycin / Q000494:pharmacology; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D004768:Enterotoxins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000502:physiology*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013211:Staphylococcus aureus; D018089:Superantigens / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017252:CD3 Complex; D016207:Cytokines; D004768:Enterotoxins; D007476:Ionophores; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D000001:Calcimycin; C031818:enterotoxin B, staphylococcal; D013755:Tetradecanoylphorbol Acetate