Variability and Robustness in T Cell Activation from Regulated Heterogeneity in Protein Levels

From Q-bio

Stochasticity in protein expression can either interfere with physiological performance or contribute to the useful diversification of biological functions for a clonal population of cells. We developed a single-cell assay to monitor how endogenous variation in the expression levels of signaling proteins influences response variability. Combining this new methodology and computer modeling to study T cell activation, we identified and characterized two key regulators of antigen-induced signaling. The CD8 coreceptor functions as an analog regulator that tunes the activation threshold, while SHP-1 phosphatase acts as a digital regulator whose level determines whether a cell is either responsive or non-responsive. Stochastic variation in the levels of these two proteins generates substantial activation response diversity among cells in a clonal population, but co-regulation in the expression of these molecules limits the extent of this effect. Together, these properties of the signaling network allow T cells to have functional flexibility without sacrificing accurate discrimination between self and foreign antigens.