Modeling Cell-Specific Dynamics and Regulation of the Common Gamma Chain Cytokines

Abstract

Many receptor families exhibit both pleiotropy and redundancy in their regulation, with multiple ligands, receptors, and responding cell populations. Any intervention, therefore, has multiple effects, confounding intuition about how to precisely manipulate signaling for therapeutic purposes. The common {gamma}-chain cytokine receptor dimerizes with complexes of the cytokines interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and their corresponding "private" receptors. These cytokines have existing uses and future potential as immune therapies due to their ability to regulate the abundance and function of specific immune cell populations. However, engineering cell specificity into a therapy is confounded by the complexity of the family across responsive cell types. Here, we build a binding-reaction model for the ligand-receptor interactions of common {gamma}-chain cytokines enabling quantitative predictions of response. We show that accounting for receptor-ligand trafficking is essential to accurately model cell response. This model accurately predicts ligand response across a wide panel of cell types under diverse experimental designs. Further, we can predict the effect and specificity of natural or engineered ligands across cell types. We then show that tensor factorization is a uniquely powerful tool to visualize changes in the input-output behavior of the family across time, cell types, ligands, and concentration. In total, these results present a more accurate model of ligand response validated across a panel of immune cell types, and demonstrate an approach for generating interpretable guidelines to manipulate the cell type-specific targeting of engineered ligands. These techniques will in turn help to study and therapeutically manipulate many other complex receptor-ligand families. Summary pointsO_LIA dynamical model of the {gamma}-chain cytokines accurately models responses to IL-2, IL-15, IL-4, and IL-7. C_LIO_LIReceptor trafficking is necessary for capturing ligand response. C_LIO_LITensor factorization maps responses across cell populations, receptors, cytokines, and dynamics to visualize cytokine specificity. C_LIO_LIAn activation model coupled with tensor factorization provides design specifications for engineering cell-specific responses. C_LI