Transforming growth factor-β1 suppresses interleukin-15-mediated interferon-γ production in human T lymphocytes

Abstract

One of the most remarkable means by which tumour cells manage to evade recognition and elimination by the immune system is the release of immunosuppressive mediators, such as interleukin (IL)-10 or transforming growth factor-β (TGF-β). For antitumour immunotherapies to reach their full potential, cytokine cocktails will have to be custom-tailored to the tumour's individual cytokine microenvironment. One of the components of such a cytokine cocktail may be interleukin (IL)-15, which has demonstrated an excellent stimulatory potential of antitumour immunity. In an in vitro model, we have previously been able to show that the negative effects of IL-10 on IL-15-mediated cytotoxic T-cell activation can be outweighed by the addition of interleukin (IL)-12. The mechanism by which TGF-β may influence the effect of IL-15 remains poorly understood, however. We have therefore taken our T-cell model further and have studied the effect of TGF-β on IL-15- mediated interferon-γ (IFN-γ) production. In activated, IL-15-stimulated peripheral blood T lymphocytes, TGF-β suppressed IFN-γ mRNA and protein levels by ≃75%. This effect was likewise observed on both CD4+ and CD8+ T cells and, in contrast to the effect of IL-10 in this system, could not be neutralized by the addition of IL-12. Thus, immunotherapy for TGF-β- producing tumours may benefit from the addition of TGF-neutralizing activity rather than IL-12.