Dual roles for class II major histocompatibility complex molecules in staphylococcal enterotoxin-induced cytokine production and in vivo toxicity.
The staphylococcal enterotoxins (SE) specifically bind to class II major histocompatibility complex (MHC) proteins, resulting in activation of monocytes and T cells. The SE cause weight loss in mice, which is dependent on T-cell stimulation and tumor necrosis factor alpha (TNF-alpha) production. Here we use a mutant of staphylococcal enterotoxin A that binds class II MHC molecules and activates monocytes but not T cells to evaluate the relative contributions of monocyte- and T-cell-stimulatory activities to in vivo toxicity. The mutant toxin did not cause weight loss in B10. BR mice but did stimulate monocyte TNF-alpha production in vitro, as did the wild-type toxin. Addition of a supernatant from toxin-activated T cells enhanced monocyte-stimulatory activity of both mutant and wild-type toxins fivefold. The effect of the supernatant could be mimicked by recombinant gamma interferon (IFN-gamma) and was inhibited by antibody to IFN-gamma. These results suggest that toxin-induced monocyte TNF-alpha production is upregulated by IFN-gamma, which likely represents the T-cell requirement in SE-mediated weight loss. Our studies thus implicate two distinct class II MHC-dependent signaling pathways for SE, the first involving direct signal transduction through class II MHC molecules mediated by either mutant or wild-type toxin and the second requiring T-cell stimulation by toxin-class II MHC complexes with consequent production of IFN-gamma. We suggest that both pathways are required for optimal monocyte TNF-alpha production in vitro and SE-induced toxicity in vivo.
Grossman
D
D
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030.
Lamphear
J G
JG
Mollick
J A
JA
Betley
M J
MJ
Rich
R R
RR
D000818:Animals; D002478:Cells, Cultured; D004768:Enterotoxins / Q000633:toxicity*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D011994:Recombinant Proteins; D013211:Staphylococcus aureus / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015431:Weight Loss / Q000187:drug effects
D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma