Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response

Abstract

Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin-2 (IL-2) signaling in a population of T cells during an immune response by combining in silico modeling and single-cell measurements in vitro. We demonstrate that IL-2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL-2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug-of-war for IL-2 between regulatory (T reg) and effector (T eff) T cells, whereby access to IL-2 can either increase the survival of T eff cells or the suppressive capacity of T reg cells. This tug-of-war is the mechanism enforcing, at the systems level, a core function of T reg cells, namely the specific suppression of survival signals for weakly activated T eff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of T reg suppression. © 2010 EMBO and Macmillan Publishers Limited.