Transforming growth factor-beta(1) suppresses interleukin-15-mediated interferon-gamma production in human T lymphocytes

One of the most remarkable means by which tumour cells manage to evade reco gnition and elimination by the immune system is the release of immunosuppre ssive mediators, such as interleukin (IL)-10 or transforming growth factor- beta (TGF-beta). For antitumour immunotherapies to reach their full potenti al, cytokine cocktails will have to be custom-tailored to the tumour's indi vidual cytokine microenvironment. One of the components of such a cytokine cocktail may be interleukin (IL)-15, which has demonstrated an excellent st imulatory potential of antitumour immunity. In an in vitro model, we have p reviously been able to show that the negative effects of IL-10 on IL-15-med iated cytotoxic T-cell activation can be outweighed by the addition of inte rleukin (IL)-12. The mechanism by which TGF-beta may influence the effect o f IL-15 remains poorly understood, however. We have therefore taken our T-c ell model further and have studied the effect of TGF-beta on IL-15-mediated interferon-gamma (IFN-gamma) production. In activated, IL-15-stimulated pe ripheral blood T lymphocytes, TGF-beta suppressed IFN-gamma mRNA and protei n levels by approximate to 75%. This effect was likewise observed on both C D4(+) and CD8(+) T cells and, in contrast to the effect of IL-10 in this sy stem, could not be neutralized by the addition of IL-12. Thus, immunotherap y for TGF-beta-producing tumours may benefit from the addition of TGF-neutr alizing activity rather than IL-12.