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Science. 2008 Aug 22;321(5892):1081-4. doi: 10.1126/science.1158013.

Variability and robustness in T cell activation from regulated heterogeneity in protein levels.

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  • 1ImmunoDynamics Group, Program in Computational Biology and Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 460, New York, NY 10065, USA.

Abstract

In T cells, the stochasticity of protein expression could contribute to the useful diversification of biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T cell activation. We found that the CD8 co-receptor fine-tunes activation thresholds, whereas the soluble hematopoietic phosphatase 1 (SHP-1) digitally regulates cell responsiveness. Stochastic variation in the expression of these proteins generates substantial diversity of activation within a clonal population of T cells, but co-regulation of CD8 and SHP-1 levels ultimately limits this very diversity. These findings reveal how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.

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