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Science 321 (5892): 1081-1084

Copyright © 2008 by the American Association for the Advancement of Science

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

Ofer Feinerman,1* Joël Veiga,1* Jeffrey R. Dorfman,1{dagger} Ronald N. Germain,2 Grégoire Altan-Bonnet1{ddagger}

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.

1 ImmunoDynamics Group, Program in Computational Biology and Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 460, New York, NY 10065, USA.
2 Lymphocyte Biology Section, Laboratory of Immunology, Program in Systems Immunology and Infectious Disease Modeling, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Building 10, Room 11N311, 10 Center Drive, MSC-1892, Bethesda, MD 20892-1892, USA.

* These authors contributed equally to this work.

{dagger} Present address: Seattle Biomedical Research Institute, 307 Westlake Avenue N, Suite 500, Seattle, WA 98109-5219, USA.

{ddagger} To whom correspondence should be addressed. E-mail: altanbonnet{at}cbio.mskcc.org


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