Interferon inhibition of IL-2-mediated lymphocyte proliferation

Interleukin-2 (IL-2) combined with hybrid human alpha interferon (IFN-alpha A/D) mediates enhanced tumor regression compared with either agent alone. To elucidate the underlying mechanism of interaction of IL-2, with its known ability to induce expansion of T lymphocytes, and IFN-alpha A/D, with its antiproliferative activity, we studied splenocytes from normal and tumor-bearing C57BL/6 mice in 5-day cultures and measured proliferation by means of a standard 4-hour 3H-thymidine incorporation assay. Potent inhibition of IL-2-induced proliferation (usually greater than 90%) resulted from high concentrations of IFN (100 to 1000 U/ml). Splenocytes from both tumor-bearing and normal mice, cultured alone or with mitomycin-treated syngeneic tumor, MCA106, exhibited similar patterns of inhibition. Unexpectedly, allostimulation with DBA/2 (H-2d) stimulators and C57BL/6 (H-2b) responders showed enhanced proliferation, most pronounced at lower IFN concentrations. Time course of IFN action revealed minimal duration of exposure necessary for inhibition to be less than 24 hours. Microfluorometric cell analysis showed the striking increase in Thy-1+ cells (55% to 96%) induced by IL-2 with parallel increase in Lyt2+ cells but almost complete disappearance of L3T4+ cells. IFN reduced IL-2-induced increase in Lyt-2+ cells (61% to 31%). These results emphasize the complexity of IL-2 and IFN interaction and the potential for dose-related antagonistic effects. This may be important in the clinical use of this combination.