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

Science, 22 August 2008
Vol. 321, Issue 5892, p. 1081-1084
DOI: 10.1126/science.1158013

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

  1. Ofer Feinerman1,*,
  2. Joël Veiga1,*,
  3. Jeffrey R. Dorfman1,,
  4. Ronald N. Germain2,
  5. Grégoire Altan-Bonnet1,
  1. 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. 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.
  1. To whom correspondence should be addressed. E-mail: altanbonnet{at}cbio.mskcc.org
  • * These authors contributed equally to this work.

  • Present address: Seattle Biomedical Research Institute, 307 Westlake Avenue N, Suite 500, Seattle, WA 98109-5219, 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.

    • Received for publication 19 March 2008.
    • Accepted for publication 3 July 2008.

    Citation:

    O. Feinerman, J. Veiga, J. R. Dorfman, R. N. Germain, and G. Altan-Bonnet, Variability and Robustness in T Cell Activation from Regulated Heterogeneity in Protein Levels. Science 321, 1081-1084 (2008).

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