Transforming growth factor-beta inhibits interleukin-12-induced production of interferon-gamma by natural killer cells: a role for transforming growth factor-beta in the regulation of T cell-independent resistance to Toxoplasma gondii.
Severe-combined immune deficient (SCID) mice have been found to resist infection with the intracellular protozoan parasite Toxoplasma gondii via interleukin (IL)-12 stimulation of interferon (IFN)-gamma production by natural killer (NK) cells. Previously, we demonstrated the presence of increased levels of transcripts for transforming growth factor-beta (TGF-beta) in the brains and lungs of SCID mice infected with T. gondii, leading us to investigate the role of TGF-beta in the mechanism of resistance to T. gondii in these mice. Stimulation of splenocytes from SCID mice with heat-killed T. gondii resulted in production of low levels of IFN-gamma and a two to threefold increase in levels of TGF-beta in the culture supernatants. Production of IFN-gamma in these cultures was increased three to fourfold by addition of anti-TGF-beta antibody. Stimulation of splenocytes from SCID mice with IL-12 in combination with either TNF-alpha or IL-1 beta resulted in production of high levels of IFN-gamma. Addition of TGF-beta to these cultures inhibited production of IFN-gamma in a dose-dependent manner. Immunohistochemical studies revealed increased levels of TGF-beta protein in the spleens of SCID mice 5 days after oral infection with the ME49 strain of T gondii, and brains of SCID mice at 18 days post-infection. However, no difference was detected in the levels of TGF-beta transcripts in the spleens of uninfected mice or mice infected for 5 days. To test whether TGF-beta could antagonize IL-12 mediated resistance to T. gondii in vivo, we administered TGF-beta to SCID mice infected with T. gondii. This treatment resulted in earlier mortality of infected mice and significantly reduced the ability of exogenous IL-12 to delay time-to-death. Administration of anti-TGF-beta to SCID mice, beginning 24 h prior to infection and every 2 days thereafter, delayed significantly time-to-death. Together, our data demonstrate that TGF-beta antagonizes the ability of IL-12 to stimulate production of IFN-gamma by splenocytes from SCID mice, and suggest a role for TGF-beta in regulation of T cell-independent resistance to T. gondii.
Hunter
C A
CA
Department of Immunology and Infectious Diseases, Palo Alto Medical Foundation, California, USA.
Bermudez
L
L
Beernink
H
H
Waegell
W
W
Remington
J S
JS
D000818:Animals; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D016513:Mice, SCID; D014122:Toxoplasma / Q000472:pathogenicity; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma