The role of interleukin 10 in interleukin is mediated T-cell responses

Interleoidn (IL)-15 is a potent T-cell stimulating actor, which has recently been used for preclinical in vivo immunotherapy. To further analyze the role of IL15 in human T-cell responses, we investigated the IL-15 effect on CD3 -stimulated peripheral human T-cells. Therefore human T-cells were purified by resetting. Cytokine release from T-cells was measured by ELISA. Cytokine mRNA expression was determined by a semiquantilativc reverse transcriptase-polymerase chain reaction (RT-PCR). We have found, that IL-15 induced a significant T-cell proliferation and T-cell activation, as indicated by upregulalion of CD25 expression. In addition, IL-15 significantly enhanced the production of IFN-γ. TNF-a and IL-10 by CDS-activated T-cells. Since IL-10 has been demonstrated to inhibit cytokine production by T-cells, we investigated whether IL-10 could influence these IL-15 induced T-cell proliferation and cytokine production. IL-10 significantly reduced the IL-15 mediated IFN-y and TNF-a production, whereas IL-15 induced T-cell proliferation and CD25 expression were not suppressed. IL-10 also inhibited IL-10 mRNA expression in IL-15 stimulated T-cells. These inhibitory effects of IL-10 were not mediated by downregulation of endogenous IL-12 levels. Kinetic experiments revealed that IL-15 induced IL-10 production by T-cells peaked at day 2, whereas maximal IFN-y and TNF-a levels were obtained after 4 days of stimulation. At the time of peak IL-10 levels, inhibition of the endogenous IL-10 effect by use of a neutralizing antibody significantly increased the IL-15 mediated IFN-y and TNF-a release from T-cells. Thus, IL-15 induced IL-10 production by T-cells could establish an autocrine feedback mechanism, which might regulate the kinetics of IL-15 mediated immune responses. These observations may be of relevance for the therapeutic use of IL-15 in vivo.