Abstract
Cell response to extracellular ligand is affected not only by ligand availability, but also by pre-existing cell-to-cell variability that enables a range of responses within a cell population. We developed a computational model that incorporates cell heterogeneity in order to investigate Jurkat T cell response to time dependent extracellular IL-2 stimulation. Our model predicted preferred timing of IL-2 oscillatory input for maximizing downstream intracellular STAT5 nuclear translocation. The modeled cytokine exposure was replicated experimentally through the use of a microfluidic platform that enabled the parallelized capture of dynamic single cell response to precisely delivered pulses of IL-2 stimulus. The in vitro results demonstrate that single cell response profiles vary with pulsatile IL-2 input at pre-equilibrium levels. These observations confirmed our model predictions that Jurkat cells have a preferred range of extracellular IL-2 fluctuations, in which downstream response is rapidly initiated. Further investigation into this filtering behavior could increase our understanding of how pre-existing cellular states within immune cell populations enable a systems response within a preferred range of ligand fluctuations, and whether the observed cytokine range corresponds to in vivo conditions.
Highlights
The cytokine Interleukin-2 (IL-2) is an essential part of a functional immune system, playing a vital part in promoting tolerance and immunity
Our model describes downstream responses of T cells upon binding IL-2, modifying a computational framework first developed by Fallon & Lauffenburger [26] to include features of interest to us associated with the earliest events of IL-2 receptor ligation and to exclude longer timescale events which are beyond the scope of our experimental context
The steps between receptor-ligand interactions to STAT5 translocation are represented in a simplified fashion by a delay function, where translocation of STAT5 is dependent on the number of receptor-ligand complexes present at the cell surface
Summary
The cytokine Interleukin-2 (IL-2) is an essential part of a functional immune system, playing a vital part in promoting tolerance and immunity. The three subunits bind IL-2 with low to intermediate affinity [6] [7, 8], but upon the stepwise formation of a heterotrimeric receptor complex, their combined properties enable efficient ligand capture and subsequent cell response [6, 9,10,11,12,13,14]. While the IL-2 specific α subunit contributes the strongest affinity for the ligand but lacks a cytosolic component, the β and γ subunits are shared with other cytokine signaling pathways and contain membrane-spanning domains to allow for the initiation of an intracellular signaling transduction in response to ligand binding. Receptor-ligand interaction results in activation of cytosolic protein tyrosine
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