TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes

Abstract

IL-12 is a macrophage-derived heterodimeric cytokine, capable of inducing proliferation, cytokine production, and cytotoxic activity of NK cells and T cells, and is critical for the development of Th1 responses. TGF-beta is an immunosuppressive cytokine that inhibits IL-12-mediated responses in NK and T cells. To determine the mechanism of action of TGF-beta, we examined its inhibitory effect on IL-12 signal-transduction pathway in T cells. Stimulation of activated T cells with IL-12 leads to tyrosine phosphorylation and activation of Jak-2 and Tyk-2 kinases and STAT3 and STAT4 transcription factors. Treatment of activated T cells with TGF-beta blocked IL-12-induced tyrosine phosphorylation and activation of both Jak-2 and Tyk-2 kinases. Furthermore, inhibition of Jak kinases by TGF-beta was associated with a decrease in tyrosine phosphorylation of STAT3 and STAT4 proteins. Abrogation of IL-12-induced Jak-Stat pathway by TGF-beta resulted in decreased T cell proliferation and IFN-gamma production, and increased apoptotic cell death. These findings highlight that TGF-beta inhibits IL-12-mediated responses by blocking IL-12 signal transduction in T cells.