Superantigen-induced anergy in cytotoxic CD8+ T cells.
This study describes the use of bacterial superantigens to investigate the mechanisms governing peripheral tolerance in CD8+ T cells. Administration of superantigens to mice activates T cells to proliferation, cytokine production, and cytotoxicity, but responding cells subsequently enter a state of hyporesponsiveness or are deleted. Superantigen-induced inactivation has so far mainly been demonstrated for CD4+ T cells. Injection of amounts of the superantigen staphylococcal enterotoxin A (SEA) that are optimal for T cell activation and which induce anergy in CD4+ T cells result in preserved responsiveness in CD8+ CTLs. In contrast, we found that intravenous injection of low concentrations of SEA induced a profound down-regulation of the cytotoxic function in SEA-reactive CD8+ TCR V beta 11+ T cells. No reduction in the number of CD8+V beta 11+ T cells was found, suggesting that anergy and not deletion is the main mechanism for the observed cytotoxic hyporesponsiveness. The cytotoxic anergy was evident 2 days after low-dose priming and remained present 4 wk later, indicating a rapid induction phase and long-lasting persistence. The anergized CD8+ T cell subset expressed lower levels of the alpha-(CD11a) chain of the cell adhesion molecule lymphocyte function-associated Ag 1 (LFA-1) and failed to mediate cytotoxicity, but retained the capacity to proliferate, express IL-2R, produce IFN-gamma, and express granzyme mRNA, which imply a partial defect in TCR-transduced signals. Taken together, these findings suggest that there is a biphasic stimulus-dependent threshold for acquiring responsiveness or anergy in CD8+ T cells.
Sundstedt
A
A
Pharmacia Oncology Immunology, Lund, Sweden.
Höidén
I
I
Hansson
J
J
Hedlund
G
G
Kalland
T
T
Dohlsten
M
M
D000818:Animals; D017635:Clonal Anergy; D017637:Clonal Deletion; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D015870:Gene Expression; D053804:Granzymes; D007108:Immune Tolerance; D066298:In Vitro Techniques; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012697:Serine Endopeptidases / Q000235:genetics; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
D004768:Enterotoxins; D016169:Lymphocyte Function-Associated Antigen-1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases