Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology.
Interleukin-12 plays a major role in immunity to intracellular pathogens by governing the development of IFNgamma-dependent host resistance. Nevertheless, unregulated IL-12 synthesis can lead to immunopathology, an outcome prevented by the concurrent expression of interleukin-10. Dendritic cells (DC) are an important source of the initial IL-12 stimulated by microbial agents. Here, we show that, following systemic triggering, DC can no longer be restimulated to produce IL-12 in vivo while continuing to respond in vitro. When infected with Toxoplasma gondii during this refractory state, mice mount impaired acute IFNgamma responses and, in the case of IL-10-deficient animals, are protected from cytokine-induced mortality. These findings demonstrate a previously unrecognized form of immunologic paralysis involving DC that can protect from infection-induced immunopathology.
Reis e Sousa
C
C
Immunobiology Laboratory, Imperial Cancer Research Fund, London, United Kingdom. caetano@icrf.icnet.uk
Yap
G
G
Schulz
O
O
Rogers
N
N
Schito
M
M
Aliberti
J
J
Hieny
S
S
Sher
A
A
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006790:Host-Parasite Interactions; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018448:Models, Immunological; D013154:Spleen / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000150:complications / Q000276:immunology* / Q000473:pathology
D000953:Antigens, Protozoan; C094052:soluble tachyzoite antigen, Toxoplasma gondii; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma