Molecular System Biology Department, Center of Molecular Immunology, Havana, Havana 11600, Cuba.
Center for Molecular Simulations, Biological Science Department, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
J Chem Inf Model. 2021 Apr 26;61(4):1913-1920. doi: 10.1021/acs.jcim.0c01417. Epub 2021 Mar 25.
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-γ 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).
白细胞介素 (IL) 2 和 IL15 是共同γ链细胞因子家族的两个成员，参与调节 T 细胞分化过程。这两种分子都使用特定的α亚基，即 IL2Rα 和 IL15Rα，并共享相同的β和γ链信号受体。特定的α亚基的存在调节了 T 细胞竞争两种可溶性细胞因子的能力，而β和γ亚基则负责信号转导。最近的实验结果指出，特定的α亚基调节了 IL2 和 IL15 诱导刺激 T 细胞分化的能力。在其他膜受体中，信号转导的结果与信号转导亚基的相互作用强度有关。在这里，我们通过结合分子动力学模拟和自由能计算来研究 IL2Rα 和 IL15Rα 如何调节其信号复合物的稳定性。我们的模拟预测，IL2Rα 的结合会破坏由 IL2 介导的β-γ 相互作用，而 IL15Rα 则具有相反的效果。这些结果解释了 IL2Rα 和 IL15Rα 调节信号转导结果的能力，并为开发更好的用于过继细胞转移 (ACT) 的 CD8 T 细胞分化方案的信号转导提供了新的策略。
