Location of Repository

T-Cell activation: a queuing theory analysis at low agonist density

By J. R. Wedagedera and Nigel John Burroughs

Abstract

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

Topics: QD, QH301
Publisher: Biophysical Society
Year: 2006
OAI identifier: oai:wrap.warwick.ac.uk:921

Suggested articles

Preview

Citations

  1. (2000). A mathematical analysis of TCR serial triggering and down-regulation. doi
  2. (2001). A reliable and safe T-cell repertoire based on low-affinity T-cell receptors. doi
  3. (1996). A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. doi
  4. (2002). Activated TCRs remain marked for internalisation after dissociation from pMHC. doi
  5. (2004). Activation-induced polarized recycling targets T-cell antigen receptors to the immunological synapse: involvement of SNARE complexes. doi
  6. (2005). Agonist/endogenous peptide-MHC heterodimers drive T-cell activation and sensitivity. doi
  7. (2000). Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. doi
  8. (2001). Autologous regulation of naive T-cell homeostasis within the T-cell compartment. doi
  9. (2004). Ca 21 signals and T lymphocytes ‘‘new mechanisms and functions in Ca 21 signalling’’. doi
  10. (2003). Calcium oscillations in T-cells: mechanisms and consequences for gene expression. doi
  11. (2001). Calculations show substantial serial engagement of T-cell receptors. doi
  12. (2004). CD4 enhances T-cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. doi
  13. (2001). CD4-independent T cells impair TCR triggering of CD4-dependent T cells: a putative mechanism for T-cell affinity maturation. doi
  14. (2003). Continuous T-cell receptor signaling required for synapse maintenance and full effector function. doi
  15. (1999). Cross-antagonism of a T-cell clone expressing two distinct T-cell receptors. doi
  16. (2003). Cutting edge: T Lymphocyte activation by repeated immunological synapse formation and intermittent signaling. doi
  17. Cytoskeletal polarisation and redistribution of cell-surface molecules during T-cell antigen recognition. doi
  18. (2000). Designing lymphocyte functional structure for optimal signal detection: voila, doi
  19. (1996). Different responses are elicited in cytotoxic T lymphocytes by different levels of T-cell receptor occupancy. doi
  20. (1993). Direct evidence for two affinity states for lymphocyte function-associated antigen 1 on activated T cells.
  21. (2002). Direct observation of ligand recognition by T cells. doi
  22. (2003). Dynamic programming of CD8 1 lymphocyte response. doi
  23. (2004). Feedback control of T-cell receptor activation. doi
  24. (2001). Functional antigen-independent synapses formed between T cells and dendritic cells. doi
  25. (2003). Investigation of early events in FCe RI-mediated signaling using a detailed mathematical model. doi
  26. (1996). Kinetic discrimination in T-cell activation. doi
  27. (1995). Kinetic proofreading in T-cell receptor signal transduction. doi
  28. (1974). Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. doi
  29. Knock-down of the Type-3 ryanodine receptor impairs sustained Ca 21 signaling via the T-cell receptor/CD3 complex. doi
  30. (1987). Ligand-receptor interactions required for commitment to the activation of the Interleukin-2 gene.
  31. (1997). Low affinity interaction of human or rat T-cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity. doi
  32. (2004). Membranes as messengers in T-cell adhesion signaling. doi
  33. (2002). Negative regulation of immunoreceptor signaling. doi
  34. (2000). On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. doi
  35. Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells.
  36. (2001). Serial triggering of many T-cell receptors by a few peptide-MHC complexes. doi
  37. (1996). Signal extinction and T-cell repolarization in T helper cell-antigen-presenting cell conjugates. doi
  38. (1997). Single cell analysis reveals regulated hierarchical T-cell antigen receptor signalling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4 1 T cells. doi
  39. (2002). Staging and resetting T-cell activation in SMACs. doi
  40. (2003). Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. doi
  41. (2004). Stop-and-go traffic to tune T-cell responses. doi
  42. (1998). Structural and functional consequences of altering a peptide MHC anchor residue. doi
  43. (2003). Study of the mechanism of TCR antagonism using dual-TCR-expressing T cells. doi
  44. (2000). T cells compete for access to antigen-bearing antigen-presenting cells. doi
  45. (2003). T-cell fitness determined by signal strength. doi
  46. (2004). T-cell killing does not require the formation of a stable mature immunological synapse. doi
  47. (2003). T-cell sensitivity and specificity—kinetic proofreading revisited. doi
  48. (2003). TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. doi
  49. (1998). The duration of antigenic stimulation determines the fate of naive and effector T cells. doi
  50. (2002). The IkB-NF-kB signalling module: temporal control and selective gene activation.
  51. (2003). The immunological synapse balances T-cell receptor signaling and degradation.
  52. (1999). The immunological synapse: a molecular machine controlling T-cell activation. doi
  53. (2002). The proliferative capacity of individual naive CD4 1 T cells is amplified by prolonged T-cell antigen receptor triggering. doi
  54. (2002). The secretory synapse: the secrets of a serial killer. doi
  55. (2002). The TCR signalosome: a dynamic structure with expanding complexity. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.