Modeling cell-specific dynamics and regulation of the common gamma chain cytokines.

Ali M Farhat,Adam C Weiner,Cori Posner,Scott M Carlson,Aaron S Meyer,Brian Orcutt-Jahns,Zoe S Kim

doi:10.1016/j.celrep.2021.109044

Ali M Farhat, Adam C Weiner + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109044

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Abstract

SUMMARYThe γ-chain receptor dimerizes with complexes of the cytokines interleukin-2 (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 because of their ability to regulate the abundance and function of specific immune cell populations. Here, we build a binding reaction model for the ligand-receptor interactions of common γ-chain cytokines, which includes receptor trafficking dynamics, enabling quantitative predictions of cell-type-specific response to natural and engineered cytokines. We then show that tensor factorization is a powerful tool to visualize changes in the input-output behavior of the family across time, cell types, ligands, and concentrations. These results present a more accurate model of ligand response validated across a panel of immune cell types as well as a general approach for generating interpretable guidelines for manipulation of cell-type-specific targeting of engineered ligands.

Highlights

Cytokines are cell signaling proteins responsible for cellular communication within the immune system
Binding interactions were modeled based on their known structural components and led to formation of receptor complexes capable of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling (Rochman et al, 2009)
We assumed that species trafficked into an endosomal compartment while continuing to produce JAK/STAT signaling and participating in binding events

Summary

Introduction

Cytokines are cell signaling proteins responsible for cellular communication within the immune system. The common g-chain (gc) receptor cytokines, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21, are integral for modulating innate and adaptive immune responses. They have existing uses and future potential as immune therapies (Leonard et al, 2019; Rochman et al, 2009). Deficiency in the IL-2 receptor IL-2Ra causes hyperproliferation in CD8+ T cells but a diminished antigen response (Goudy et al, 2013). These examples show how gc receptor cytokines coordinate a dynamic balance of immune cell abundance and function

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