Transforming growth factor‐β inhibits interleukin‐12‐induced production of interferon‐γ by natural killer cells: A role for transforming growth factor‐β in the regulation of T cell‐independent resistance to Toxoplasma gondii

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Abstract
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)-γ production by natural killer (NK) cells. Previously, we demonstrated the presence of increased levels of transcripts for transforming growth factor-beta (TGF-β) in the brains and lungs of SCID mice infected with T. gondii, leading us to investigate the role of TGF-β 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-γ and a two to threefold increase in levels of TGF-β in the culture supernatants. Production of IFN-γ in these cultures was increased three to fourfold by addition of anti-TGF-β antibody. Stimulation of splenocytes from SCID mice with IL-12 in combination with either TNF-α or IL-1β resulted in production of high levels of IFN-γ. Addition of TGF-β to these cultures inhibited production of IFN-γ in a dose-dependent manner. Immunohistochemical studies revealed increased levels of TGF-β 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-β transcripts in the spleens of uninfected mice or mice infected for 5 days. To test whether TGF-β could antagonize IL-12 mediated resistance to T. gondii in vivo, we administered TGF-β 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-β 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-β antagonizes the ability of IL-12 to stimulate production of IFN-γ by splenocytes from SCID mice, and suggest a role for TGF-β in regulation of T cell-independent resistance to T. gondii.

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