Increased expression of the IL-2R beta chain was subsequently identified on post-therapy NK cells, suggesting these cells may have acquired increased functional IL-2 responsiveness due to up-regulation of intermediate-affinity cell-surface IL-2 receptors. Only low levels of IL-2 binding were detected in 125I-IL-2 binding assays on post-therapy NK cells, however, and it was concluded that some other component, in addition to the beta chain, was required in order to constitute an intermediate-affinity IL-2 receptor.
Using an anti-beta chain mAb to precipitate IL-2/IL-2 receptor complexes, an IL-2R gamma subunit was subsequently identified. Only low levels of gamma chain relative to beta chain were detected on post-IL-2 therapy NK cells, consistent with the hypothesis that gamma chain is required for formation of intermediate-affinity IL-2 receptors and that it was absent from the majority of the IL-2 receptors expressed on post-therapy NK cells. The surprising finding was also made that the IL-2R gamma chain is able to directly interact with IL-2 and may thus influence receptor affinity by contributing contact sites for IL-2 binding. This unexpected finding has allowed the development of a revised model of IL-2 receptor structure depicting the predicted sites of interaction of IL-2 with the respective alpha, beta, and gamma receptor subunits.
