Superantigens anergize cytokine production but not cytotoxicity in vivo.
We have investigated the effect of the superantigen staphylococcal enterotoxin A (SEA) on the balance between T-cell response and non-responsiveness in T-cell receptor (TcR) V beta 3 transgenic mice. One injection of SEA resulted in a substantial activation of TcR V beta 3+ cells, whereas T cells from mice injected with repeated doses of SEA displayed a diminished response to a subsequent in vitro challenge. The reduced responsiveness became apparent when SEA was injected multiple times with short intervals. Proliferation and cytokine production in anergized T cells were severely reduced when stimulated with SEA in vitro, whereas cytotoxic T lymphocyte (CTL) activity remained unaffected. The dichotomy between these functions was examined in vitro with respect to different T-cell subsets. The total number of CD4+ T cells was reduced in the hyporesponsive spleens, compatible with cell deletion. The remaining CD4+ TcR V beta 3+ T cells showed anergy of all tested functions and did not respond to exogenous interleukin-2 (IL-2). In contrast, there was an expansion of CD8+ TcR V beta 3+ T cells with an intact cytotoxic activity. The in vitro proliferation and production of cytokines in the CD8+ compartment was impaired, but could be partially restored in the presence of exogenously added IL-2. Analysis of the cytokine response to SEA in vivo showed that IL-2 and tumour necrosis factor (TNF) were mainly produced by CD4+ T cells, while interferon-gamma (IFN-gamma) was predominantly released by CD8+ T cells. Induction of anergy resulted in a reduction of IL-2 and TNF mRNA levels, frequencies of producing cells as well as serum protein content. In contrast, there was only a moderate influence on the IFN-gamma level in vivo. The results suggest that SEA-induced hyporesponsiveness involves CD4+ cell deletion and a failure to produce cytokines in the remaining CD4+ T-cell compartment, while IFN-gamma production and cytotoxicity in the CD8+ T-cell compartment stay relatively intact.
Sundstedt
A
A
Kabi Pharmacia Therapeutics, Lund, Sweden.
Dohlsten
M
M
Hedlund
G
G
Höidén
I
I
Björklund
M
M
Kalland
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004334:Drug Administration Schedule; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology*; D007369:Interferon Inducers / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D016827:CD8 Antigens; D016207:Cytokines; D004768:Enterotoxins; D007369:Interferon Inducers; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal