Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects.
Tumor necrosis factor (TNF, TNFalpha) is implicated in various pathophysiological processes and can be either protective, as in host defense, or deleterious, as in autoimmunity or toxic shock. To uncover the in vivo functions of TNF produced by different cell types, we generated mice with TNF ablation targeted to various leukocyte subsets. Systemic TNF in response to lipopolysaccharide was produced mainly by macrophages and neutrophils. This source of TNF was indispensable for resistance to an intracellular pathogen, Listeria, whereas T-cell-derived TNF was important for protection against high bacterial load. Additionally, both T-cell-derived TNF and macrophage-derived TNF had critical and nonredundant functions in the promotion of autoimmune hepatitis. Our data suggest that T-cell-specific TNF ablation may provide a therapeutic advantage over systemic blockade.
Grivennikov
Sergei I
SI
Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences and Belozersky Institute of Physico-Chemical Biology, 32 Vavilov Str., 119991 Moscow, Russia.
Tumanov
Alexei V
AV
Liepinsh
Dmitry J
DJ
Kruglov
Andrei A
AA
Marakusha
Boris I
BI
Shakhov
Alexander N
AN
Murakami
Takaya
T
Drutskaya
Ludmila N
LN
Förster
Irmgard
I
Clausen
Björn E
BE
Tessarollo
Lino
L
Ryffel
Bernhard
B
Kuprash
Dmitry V
DV
Nedospasov
Sergei A
SA
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D003433:Crosses, Genetic; D017353:Gene Deletion; D005822:Genetic Vectors; D008087:Listeria / Q000472:pathogenicity; D008099:Liver / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D048069:Tumor Necrosis Factors