Characterization of Lymphokine-Activated Killing by Human Peripheral Blood Mononuclear Cells Stimulated with Interleukin 2 (IL-2) Analogs Specific for the Intermediate Affinity IL-2 Receptor
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Abstract
Interleukin 2-stimulated human peripheral blood mononuclear cells (PBMC) generate
lymphokine-activated killing (LAK). Using the IL-2 analogs R38A and F42K, which interact
primarily with the beta and gamma subunits of the IL-2 receptor, we assessed the roles
of IL-2R beta gamma and the high-affinity IL-2 receptor complex in LAK activation.
Although the kinetics of LAK activation were identical, lytic activity was approximately
30% lower and proliferation was up to 55% lower in those PBMC stimulated by R38A or
F42K than in those exposed to wild-type IL-2. The percentage of cells expressing cell-surface
markers such as CD3, CD4, CD8, and CD16 was not significantly different after treatment
with wild-type IL-2, R38A, or F42K; however, the proportion of cells expressing IL-2R
alpha increased dramatically in response to stimulation by F42K (30%) compared to
stimulation by either rIL-2 or R38A (15%). In addition, by Day 7 the concentration
of soluble IL-2R alpha in analog-stimulated LAK culture supernatants was 50-75% less
than that from wild-type IL-2-cultured cells. These findings suggest that interaction
of IL-2 with IL-2R beta gamma alone is sufficient for both proliferation and the generation
of LAK, and that stimulation with subunit-specific IL-2 analogs results in differential
regulation of the IL-2R alpha on human LAK cells.