SYNERGISTIC EFFECTS OF IL-7 AND IL-12 ON HUMAN T-CELL ACTIVATION

We have previously demonstrated that human rIL-12 alone can augment th e development of cytotoxic activity in stimulated CD8(+) T cells. The present study was undertaken to examine the interactions of rIL-7 and rIL-12 on human peripheral blood T cell activation and CTL differentia tion. Purified T lymphocytes were pulsed overnight with immobilized al pha-CD3 and then cultured for 3 additional days with IL-7 and/or IL-12 . The combination of IL-7 and IL-12 synergistically enhanced the proli feration of either fresh CD3(+) T cells or an IL-2-dependent CD4(+) T cell line, Kit-225-K6. This synergy was seen on both subsets of T cell s; however, CD8(+) T cells were usually more responsive to IL-7 and IL -12 at lower concentrations than were CD4(+) T cells. Furthermore, the se cytokines additively/synergistically augmented the cytotoxic activi ty of CD8(+) T cells. Abs to IL-2 and IL-2R alpha blocked the synergis tic effect on proliferation of CD4(+) T cells, but had a minimal effec t on the synergistic response of the proliferative and cytotoxic activ ity of CD8(+) T cells. Examination of the effects of IL-7 and IL-12 on the expression of IL-12 receptor on T cells revealed an increase in t he subunit of IL-12R by IL-7 as determined by flow cytometric analysis . We analyzed the effects on IFN-gamma production by CD8(+) T cells an d found that IL-7 alone did not induce detectable levels of IFN-gamma production but together with IL-12 it synergistically enhanced the pro duction of IFN-gamma We also found that IFN-gamma was probably not req uired for enhanced CTL activity of CD8(+) T cells, because Ab to human IFN-gamma did not block additive/synergistic effects of either cytoki ne. The synergistic stimulatory activity of IL-7 and IL-12 may be of s ignificance in vivo and may provide an alternative mechanism of stimul ating T cells for use in immunotherapy.