Involvement of NK1+ T cells and their IFN-gamma production in the generalized Shwartzman reaction.
IL-12 (or LPS) priming and subsequent challenge by LPS produces the generalized Shwartzman reaction. IFN-gamma induced by IL-12 is a crucial cytokine in the priming phase. In vivo depletion of both NK cells and NK1+ alphabeta T cells of mice by anti-NK1.1 Ab greatly reduced the elevation of serum IFN-gamma induced by IL-12 and significantly reduced mortality after subsequent injection of LPS, whereas depletion of NK cells alone by anti-asialo GM1 Ab only partially decreased serum IFN-gamma, and lethality was not changed. Cell sorting and culture experiments confirmed that liver NK1+ alphabeta T cells of IL-12-injected mice produced greater amounts of IFN-gamma than did liver NK cells. MHC class I-deficient mice of C57BL/6 background, which lack a majority of NK1+ alphabeta T cells, produced low amounts of IFN-gamma by IL-12; no mortality was observed after the LPS challenge. However, production of TNF-alpha in the second phase (after LPS challenge) was not inhibited by depletion of NK cells alone or both subsets. IL-12 and subsequent LPS challenge activated NK1+ alphabeta T cells in the liver and induced strong cytotoxicity of these cells not only against tumor cells (including Fas-negative tumors) but also against a syngeneic hepatocyte cell line. Our findings show that IFN-gamma produced by NK1+ alphabeta T cells is essential for the IL-12 priming of the Shwartzman reaction, and the autoreactivity of NK1+ alphabeta T cells in the liver is involved in the hepatic disorders that are sometimes caused by IL-12, LPS, or the generalized Shwartzman reaction.
Ogasawara
K
K
Department of Microbiology, Tohoku University School of Dentistry, Sendai, Japan.
Takeda
K
K
Hashimoto
W
W
Satoh
M
M
Okuyama
R
R
Yanai
N
N
Obinata
M
M
Kumagai
K
K
Takada
H
H
Hiraide
H
H
Seki
S
S
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D012790:Shwartzman Phenomenon / Q000276:immunology* / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D018949:Antigens, CD1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma