Immunoregulatory role of IL-10 during superantigen-induced hyporesponsiveness in vivo.
Injection of the superantigen staphylococcal enterotoxin A (SEA) to mice rapidly elicits production of the Th1-related pro-inflammatory cytokines IL-2, TNF, and IFN-gamma, while repeated SEA challenges transduce a hyporesponsive state characterized by T cell deletions and anergy in the remaining SEA-reactive T cells. In the present study we show that exposure to SEA promotes the development of immunoregulatory IL-10-producing Th cells. Serum IL-10 was undetectable in mice given a priming injection of SEA, but rose to considerable levels when a SEA challenge was administered 4 days later. This coincided with maintained IL-2 production and superinduction of TNF, IFN-gamma, and IL-4. Interestingly, administration of a second SEA challenge resulted in high serum levels of IL-10, but the production of all other studied cytokines (IL-2, TNF, IFN-gamma, and IL-4) was impaired. The IL-10 production was sustained after a third and a fourth SEA challenge in the complete absence of IL-2, IFN-gamma, and IL-4. Pretreatment of mice with neutralizing anti-lL-10 mAb before the SEA challenges substantially enhanced IFN-gamma and TNF serum levels, but failed to rescue IL-2 production. Depletion of T cells with anti-CD4 or anti-CD8 mAb indicated that CD4+ T cells were crucial for SEA-induced IL-10 production. This finding was confirmed using CD4- and CD8- knockout mice. We conclude that repeated SEA challenges promote an IL-10-producing Th cell subset ("Th10" profile), which exerts an immunoregulatory effect by suppressing IFN-gamma and TNF production.
Sundstedt
A
A
Pharmacia and Upjohn, Lund, Sweden.
Höiden
I
I
Rosendahl
A
A
Kalland
T
T
van Rooijen
N
N
Dohlsten
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004334:Drug Administration Schedule; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D007369:Interferon Inducers / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology*
D004768:Enterotoxins; D007369:Interferon Inducers; D007376:Interleukin-2; D015848:Interleukin-5; D018089:Superantigens; D016753:Interleukin-10; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma