T-Cell activation: a queuing theory analysis at low agonist density
Wedagedera, J. R. and Burroughs, Nigel John. (2006) T-Cell activation: a queuing theory analysis at low agonist density. Biophysical Journal, Vol.91 (No.5). pp. 1604-1618. ISSN 0006-3495
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Official URL: http://dx.doi.org/10.1529/biophysj.105.066001
We analyze a simple linear triggering model of the T-cell receptor (TCR) within the framework of queuing theory, in which TCRs enter the queue upon full activation and exit by downregulation. We fit our model to four experimentally characterized threshold activation criteria and analyze their specificity and sensitivity: the initial calcium spike, cytotoxicity, immunological synapse formation, and cytokine secretion. Specificity characteristics improve as the time window for detection increases, saturating for time periods on the timescale of downregulation; thus, the calcium spike (30 s) has low specificity but a sensitivity to single-peptide MHC ligands, while the cytokine threshold (1 h) can distinguish ligands with a 30% variation in the complex lifetime. However, a robustness analysis shows that these properties are degraded when the queue parameters are subject to variation—for example, under stochasticity in the ligand number in the cell-cell interface and population variation in the cellular threshold. A time integration of the queue over a period of hours is shown to be able to control parameter noise efficiently for realistic parameter values when integrated over sufficiently long time periods (hours), the discrimination characteristics being determined by the TCR signal cascade kinetics (a kinetic proofreading scheme). Therefore, through a combination of thresholds and signal integration, a T cell can be responsive to low ligand density and specific to agonist quality. We suggest that multiple threshold mechanisms are employed to establish the conditions for efficient signal integration, i.e., coordinate the formation of a stable contact interface.
|Item Type:||Journal Article|
|Subjects:||Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
|Divisions:||Faculty of Science > Mathematics|
|Library of Congress Subject Headings (LCSH):||T cells -- Receptors, Immune system, Major histocompatibility complex|
|Journal or Publication Title:||Biophysical Journal|
|Official Date:||September 2006|
|Page Range:||pp. 1604-1618|
|Access rights to Published version:||Open Access|
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