Differential Effects of IL2Rα and IL15Rα over the Stability of the Common Beta-Gamma Signaling Subunits of the IL2 and IL15 Receptors.

Interleukin (IL) 2 and IL15 are two members of the common gamma chain cytokine family, involved in the regulation of the T cell differentiation process. Both molecules use a specific alpha subunit, IL2Rα and IL15Rα, and share the same beta and gamma chains signaling receptors. The presence of the specific alpha subunit modulates the T cell ability to compete for both soluble cytokines while the beta and gamma subunits are responsible for the signal transduction. Recent experimental results point out that the specific alpha subunits modulate the capacity of IL2 and IL15 to induce the differentiation of stimulated T cells. In other membrane receptors, the outcome of the signal transduction has been associated with the strength of the interaction of the signaling subunits. Here, we investigate how IL2Rα and IL15Rα modulate the stability of their signaling complexes by combining molecular dynamics simulations and free energy calculations. Our simulations predict that IL2Rα binding destabilizes the β-γc interaction mediated by IL2, while IL15Rα has the opposite effect. These results explain the ability of IL2Rα and IL15Rα to modulate the signaling outcome and suggest new strategies for the development of better CD8+ T cell differentiation protocols for adoptive cell transfer (ACT).