IL-12-induced IL-10 production by human T cells as a negative feedback for IL-12-induced immune responses

IL-12 is an important initiator of cellular immune responses. This involves a positive feedback mechanism via IFN-gamma, which is abrogated when the pathogen that induces IL-12 production by the macrophage has been cleared. Here, we studied IL-10 as an additional negative regulator of IL-12-induced immune responses. Our results showed that upon stimulation with CD2 mAb, IL-12 was capable of inducing human T cells to produce IL-10. IL-12 was able to induce IL-10 production in primary T cells in the absence or the presence of accessory cells and in short-term cultures of established T cell clones. Moreover, T cell clones that had been cultured for longer periods in the presence of IL-12, when restimulated in the absence of IL-12, still produced high amounts of IL-10. Furthermore, we demonstrated that IL-10-mediated inhibition of T cell proliferation was dose dependent and depended on the time of addition of IL-10 and on the IL-12 concentration in culture. IL-10 has been identified as a dominant inhibitor of IL-12 production by APCs. The finding that IL-12 is capable of potently inducing its own inhibitor shows that the immune system is equipped with an intrinsic negative feedback mechanism that limits ongoing T cell activation. This indicates that the kinetics of T cell responses seem to be regulated by the ratio of IL-12 and IL-10 levels, which may gradually decline during the immune response.