High-Affinity CD25-Binding IL-2 Mutants Potently Stimulate Persistent T Cell Growth

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Abstract
We have used directed evolution to construct IL-2 mutants that bind the IL-2 α receptor subunit (IL-2Rα, CD25) with affinities comparable to that of the IL-15−IL-15 α receptor subunit (IL-15Rα) interaction. T cells proliferate for up to 6 days following a 30 minute incubation with these IL-2 mutants, which may lead to potential applications for cancer and viral immunotherapy. Several alternative mechanisms have been proposed to explain the contrasting effects of IL-2 and IL-15 on T cell proliferation and death. These IL-2 mutants exhibit T cell growth response−receptor occupancy curves indistinguishable from that for IL-15, suggesting that much of the difference between wild-type IL-2 and IL-15 effects arises simply from their 1000-fold differing affinities for their private α receptor subunits.