Oscillatory IL-2 stimulus reveals pertinent signaling timescales of T cell responsiveness.

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.