Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Models of signalling networks - what cell biologists can gain from them and give to them.
K. A. Janes and D. A. Lauffenburger (2013)
J. Cell Sci. 126, 1913-1921
   Abstract »    Full Text »    PDF »
T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy.
S. Zhong, K. Malecek, L. A. Johnson, Z. Yu, E. Vega-Saenz de Miera, F. Darvishian, K. McGary, K. Huang, J. Boyer, E. Corse, et al. (2013)
PNAS 110, 6973-6978
   Abstract »    Full Text »    PDF »
Cell-to-Cell Variability Analysis Dissects the Plasticity of Signaling of Common {gamma} Chain Cytokines in T Cells.
J. W. Cotari, G. Voisinne, O. E. Dar, V. Karabacak, and G. Altan-Bonnet (2013)
Science Signaling 6, ra17
   Abstract »    Full Text »    PDF »
Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism.
P. Francois, G. Voisinne, E. D. Siggia, G. Altan-Bonnet, and M. Vergassola (2013)
PNAS 110, E888-E897
   Abstract »    Full Text »    PDF »
Dynamics of the DNA damage response: insights from live-cell imaging.
K. Karanam, A. Loewer, and G. Lahav (2013)
Briefings in Functional Genomics 12, 109-117
   Abstract »    Full Text »    PDF »
Genetic Variants Contribute to Gene Expression Variability in Humans.
A. M. Hulse and J. J. Cai (2013)
Genetics 193, 95-108
   Abstract »    Full Text »    PDF »
Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming.
J. Banchereau, S. Zurawski, L. Thompson-Snipes, J.-P. Blanck, S. Clayton, A. Munk, Y. Cao, Z. Wang, S. Khandelwal, J. Hu, et al. (2012)
PNAS 109, 18885-18890
   Abstract »    Full Text »    PDF »
Selection pressure exerted by imatinib therapy leads to disparate outcomes of imatinib discontinuation trials.
M. Tang, J. Foo, M. Gonen, J. Guilhot, F.-X. Mahon, and F. Michor (2012)
Haematologica 97, 1553-1561
   Abstract »    Full Text »    PDF »
K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis.
K. Singh, P. Deshpande, G. Li, M. Yu, S. Pryshchep, M. Cavanagh, C. M. Weyand, and J. J. Goronzy (2012)
PNAS 109, E1629-E1637
   Abstract »    Full Text »    PDF »
Stable IL-2 Decision Making by Endogenous c-Fos Amounts in Peripheral Memory T-helper Cells.
H. Bendfeldt, M. Benary, T. Scheel, S. Frischbutter, A. Abajyan, A. Radbruch, H. Herzel, and R. Baumgrass (2012)
J. Biol. Chem. 287, 18386-18397
   Abstract »    Full Text »    PDF »
Inhibitory Receptors on Lymphocytes: Insights from Infections.
P. M. Odorizzi and E. J. Wherry (2012)
J. Immunol. 188, 2957-2965
   Abstract »    Full Text »    PDF »
Polyfunctional responses by human T cells result from sequential release of cytokines.
Q. Han, N. Bagheri, E. M. Bradshaw, D. A. Hafler, D. A. Lauffenburger, and J. C. Love (2012)
PNAS 109, 1607-1612
   Abstract »    Full Text »    PDF »
Circadian Variation of the Response of T Cells to Antigen.
E. E. Fortier, J. Rooney, H. Dardente, M.-P. Hardy, N. Labrecque, and N. Cermakian (2011)
J. Immunol. 187, 6291-6300
   Abstract »    Full Text »    PDF »
Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells.
M. Tang, M. Gonen, A. Quintas-Cardama, J. Cortes, H. Kantarjian, C. Field, T. P. Hughes, S. Branford, and F. Michor (2011)
Blood 118, 1622-1631
   Abstract »    Full Text »    PDF »
T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters.
B. N. Manz, B. L. Jackson, R. S. Petit, M. L. Dustin, and J. Groves (2011)
PNAS 108, 9089-9094
   Abstract »    Full Text »    PDF »
Flow Cytometry, Amped Up.
C. Benoist and N. Hacohen (2011)
Science 332, 677-678
   Abstract »    Full Text »    PDF »
Nuclear Origins of Cell-to-Cell Variability.
Z. Waks and P. A. Silver (2011)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy.
S. C. Hoffmann, A. Cohnen, T. Ludwig, and C. Watzl (2011)
J. Immunol. 186, 2757-2764
   Abstract »    Full Text »    PDF »
Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers.
C. A. Rivet, A. S. Hill, H. Lu, and M. L. Kemp (2011)
Mol. Cell. Proteomics 10, M110.003921
   Abstract »    Full Text »    PDF »
CTLs respond with activation and granule secretion when serving as targets for T-cell recognition.
O. Milstein, D. Hagin, A. Lask, S. Reich-Zeliger, E. Shezen, E. Ophir, Y. Eidelstein, R. Afik, Y. E. Antebi, M. L. Dustin, et al. (2011)
Blood 117, 1042-1052
   Abstract »    Full Text »    PDF »
Fine Tuning of the Threshold of T Cell Selection by the Nck Adapters.
E. Roy, D. Togbe, A. Holdorf, D. Trubetskoy, S. Nabti, G. Kublbeck, S. Schmitt, A. Kopp-Schneider, F. Leithauser, P. Moller, et al. (2010)
J. Immunol. 185, 7518-7526
   Abstract »    Full Text »    PDF »
Perspectives for Computer Modeling in the Study of T Cell Activation.
J. Coward, R. N. Germain, and G. Altan-Bonnet (2010)
Cold Spring Harb Perspect Biol 2, a005538
   Abstract »    Full Text »    PDF »
Cutting Edge: Inhibitory Effects of CD4 and CD8 on T Cell Activation Induced by High-Affinity Noncognate Ligands.
A. S. Chervin, J. D. Stone, N. A. Bowerman, and D. M. Kranz (2009)
J. Immunol. 183, 7639-7643
   Abstract »    Full Text »    PDF »
The Activation Threshold of CD4+ T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla.
T. L. Stephen, A. Tikhonova, J. M. Riberdy, and T. M. Laufer (2009)
J. Immunol. 183, 5554-5562
   Abstract »    Full Text »    PDF »
Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels.
K. Takada and S. C. Jameson (2009)
J. Exp. Med. 206, 2253-2269
   Abstract »    Full Text »    PDF »
Self-Peptides Prolong Survival in Murine Autoimmunity via Reduced IL-2/IL-7-Mediated STAT5 Signaling, CD8 Coreceptor, and V{alpha}2 Down-Regulation.
J. Gutermuth, K. E. Nograles, F. Miyagawa, E. Nelson, Y.-H. Cho, and S. I. Katz (2009)
J. Immunol. 183, 3130-3138
   Abstract »    Full Text »    PDF »
The Impact of TCR-Binding Properties and Antigen Presentation Format on T Cell Responsiveness.
A. S. Chervin, J. D. Stone, P. D. Holler, A. Bai, J. Chen, H. N. Eisen, and D. M. Kranz (2009)
J. Immunol. 183, 1166-1178
   Abstract »    Full Text »    PDF »
KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs.
J. Lin, A. Harding, E. Giurisato, and A. S. Shaw (2009)
Mol. Cell. Biol. 29, 2082-2091
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882