The Library

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

Tools

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

Preview

PDF
WRAP_Burroughs_Tcell.pdf - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (306Kb)

Official URL: http://dx.doi.org/10.1529/biophysj.105.066001

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.

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
Publisher:	Biophysical Society
ISSN:	0006-3495
Date:	September 2006
Volume:	Vol.91
Number:	No.5
Page Range:	pp. 1604-1618
Identification Number:	10.1529/biophysj.105.066001
Status:	Peer Reviewed
Access rights to Published version:	Open Access
References:	1. M.L. Dustin, T.G. Bivona and M.R. Philips, Membranes as messengers in T-cell adhesion signaling, Nat. Immunol. 5 (2004), pp. 363–372. 2. G. Bossi, C. Trambas, S. Booth, R. Clark, J. Stinchcombe and G.M. Griffiths, The secretory synapse: the secrets of a serial killer, Immunol. Rev. 189 (2002), pp. 152–160. 3. B. Hemmer, I. Stefanova, M. Vergelli, R.N. Germain and R. Martin, Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells, J. Immunol. 160 (1998), pp. 5807–5814. 4. Y. Itoh and R.N. Germain, Single cell analysis reveals regulated hierarchical T-cell antigen receptor signalling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells, J. Exp. Med. 186 (1997), pp. 757–766. 5. S. Valitutti, S. Muller, M. Dessing and A. Lanzavecchia, Different responses are elicited in cytotoxic T lymphocytes by different levels of T-cell receptor occupancy, J. Exp. Med. 183 (1996), pp. 1917–1921. 6. G. Lezzi, K. Karjalainen and A. Lanzavecchia, The duration of antigenic stimulation determines the fate of naive and effector T cells, Immunity 8 (1998), pp. 89–95. 7. M.A. Purbhoo, D.J. Irvine, J.B. Huppa and M.M. Davis, T-cell killing does not require the formation of a stable mature immunological synapse, Nat. Immunol. 5 (2004), pp. 524–530. 8. M. Faroudi, R. Zaru, P. Paulet, S. Müller and S. Valitutti, Cutting edge: T Lymphocyte activation by repeated immunological synapse formation and intermittent signaling, J. Immunol. 171 (2003), pp. 1128–1132. 9. J.B. Huppa, M. Gleimer, C. Sumen and M.M. Davis, Continuous T-cell receptor signaling required for synapse maintenance and full effector function, Nat. Immunol. 4 (2003), pp. 749–755. 10. A.V. Gett, F. Sallusto, A. Lanzavecchia and J. Geginat, T-cell fitness determined by signal strength, Nat. Immunol. 4 (2003), pp. 355–360. 11. M.J.B. van Stipdonk, G. Hardenberg, M.S. Bijker, E.E. Lemmens, N.M. Droin, D.R. Green and S.P. Schoenberger, Dynamic programming of CD8+ lymphocyte response, Nat. Immunol. 4 (2003), pp. 361–365. 12. A.G. Schrum and L.A. Turka, The proliferative capacity of individual naive CD4+ T cells is amplified by prolonged T-cell antigen receptor triggering, J. Exp. Med. 196 (2002), pp. 793–803. 13. M. Gunzer, A. Schafer, S. Borgmann, S. Gragge, K.S. Zanker, E.B. Brocker, E. Kampgen and P. Friedl, Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential, Immunity 13 (2000), pp. 323–332. 14. S. Valitutti, S. Muller, M. Cella, E. Padovan and A. Lanzavecchi, Serial triggering of many T-cell receptors by a few peptide-MHC complexes, Nature. 375 (1995), pp. 148–151. 15. C. Chan, A.J.T. George and J. Stark, Cooperative enhancement of specificity in a lattice of T-cell receptors, Proc. Natl. Acad. Sci. USA 98 (2001), pp. 5758–5763. 16. C. Chan, J. Stark and A.J.T. George, Feedback control of T-cell receptor activation, Proc. Roy. Soc. Biol. 271 (2004), pp. 931–939. 17. A. Noest, Designing lymphocyte functional structure for optimal signal detection: voila, T cells, J. Theor. Biol. 207 (2000), pp. 195–216. 18. H.A. van den Berg, D.A. Rand and N.J. Burroughs, A reliable and safe T-cell repertoire based on low-affinity T-cell receptors, J. Theor. Biol. 209 (2001), pp. 465–486. 19. K.-H. Lee, A.R. Dinner, C. Tu, G. Campi, S. Raychaudhuri, R. Varma, T.N. Sims, W.R. Burack, H. Wu, J. Wang, O. Kanagawa, M. Markiewicz, P.M. Allen, M.L. Dustin, A.K. Chakraborty and A.S. Shaw, The immunological synapse balances T-cell receptor signaling and degradation, Science 302 (2003), pp. 1218–1222. 20. W. S McKeithan, Kinetic proofreading in T-cell receptor signal transduction, Proc. Natl. Acad. Sci. USA 92 (1995), pp. 5042–5046. 21. J.D. Rabinowitz, C. Beeson, D.S. Lyons, M.M. Davis and H.M. McConnell, Kinetic discrimination in T-cell activation, Proc. Natl. Acad. Sci. USA 93 (1996), pp. 1401–1405. 22. C. Chan, A.J.T. George and J. Stark, T-cell sensitivity and specificity—kinetic proofreading revisited, Discr. Contin. Dynam. Sys. B. 3 (2003), pp. 343–360. 23. I. Stefanova, B. Hemmer, M. Vergelli, R. Martin, W.E. Biddison and R.N. Germain, TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways, Nat. Immunol. 4 (2003), pp. 248–254. 24. A. Veillette, S. Latour and D. Davidson, Negative regulation of immunoreceptor signaling, Annu. Rev. Immunol. 20 (2002), pp. 669–707. 25. J.R. Faeder, W.S. Hlavacek, I. Reischl, M.L. Blinov, H. Metzger, A. Redondo, C. Wofsy and B. Goldstein, Investigation of early events in FCvar epsilon RI-mediated signaling using a detailed mathematical model, J. Immunol. 170 (2003), pp. 3769–3781. 26. D.J. Irvine, M.A. Purbhoo, M. Krogsgaard and M.M. Davis, Direct observation of ligand recognition by T cells, Nature 419 (2002), pp. 845–849. 27. P. Revy, M. Sospedra, B. Barbour and A. Trautmann, Functional antigen-independent synapses formed between T cells and dendritic cells, Nat. Immunol. 2 (2001), pp. 925–931. 28. A. Weiss, R. Shields, M. Newton, B. Manger and J. Imboden, Ligand-receptor interactions required for commitment to the activation of the Interleukin-2 gene, J. Immunol. 138 (1987), pp. 2169–2176. 29. G. Iezzi, K. Karjalainen and A. Lanzavecchia, The duration of antigenic stimulation determines the fate of naive and effector T cells, Immunity 8 (1998), pp. 89–95. 30. N. Schwarzmann, S. Kunerth, K. Weber, G.W. Mayr and A.H. Guse, Knock-down of the Type-3 ryanodine receptor impairs sustained Ca2+ signaling via the T-cell receptor/CD3 complex, J. Biol. Chem. 277 (2002), pp. 50636–50642. 31. C. Wulfing, B. Purtic, J. Klem and J.D. Schatzle, Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing, Proc. Natl. Acad. Sci. USA 100 (2003), pp. 7767–7772. 32. A.P. van der Merwe, S.J. Davis, A.S. Shaw and M.L. Dustin, Cytoskeletal polarisation and redistribution of cell-surface molecules during T-cell antigen recognition, Semin. Immunol. 12 (2000), pp. 5–21. 33. M. Krummel, M.D. Sjaastad, C. Wülfing and M.M. Davis, Differential clustering of CD4 and CD3ζ during T-cell recognition, Science 289 (2000), pp. 1349–1352. 34. B.A. Freiberg, H. Kupfer, W. Maslanik, J. Delli, J. Kappler, D.M. Zaller and A. Kupfer, Staging and resetting T-cell activation in SMACs, Nat. Immunol. 3 (2002), pp. 911–917. 35. A. Hoffmann, A. Levchenko, M.L. Scott and D. Baltimore, The IκB-NF-κB signalling module: temporal control and selective gene activation, Science 298 (2002), pp. 1241–1245. 36. R.S. Lewis, Calcium oscillations in T-cells: mechanisms and consequences for gene expression, Biochem. Soc. Trans. 31 (2003), pp. 925–929. 37. B.N. Dittel, I. Stefanova, R.N. Germain and C.A. Janeway, Cross-antagonism of a T-cell clone expressing two distinct T-cell receptors, Immunity 11 (1999), pp. 289–298. 38. M.L. Dustin, Stop-and-go traffic to tune T-cell responses, Immunity 21 (2004), pp. 305–314. 39. J.J. Hopfield, Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity, Proc. Natl. Acad. Sci. USA 71 (1974), pp. 4135–4139. 40. G. Werlen and E. Palmer, The TCR signalosome: a dynamic structure with expanding complexity, Curr. Opin. Immunol. 14 (2002), pp. 299–305. 41. D. Coombs, A.M. Kalergis, S.G. Nathenson, C. Wofsy and B. Goldstein, Activated TCRs remain marked for internalisation after dissociation from pMHC, Nat. Immunol. 3 (2002), pp. 926–931. 42. A. Grakoui, S.K. Bromley, C. Sumen, M.M. Davis, A.S. Shaw, P.M. Allen and M.L. Dustin, The immunological synapse: a molecular machine controlling T-cell activation, Science 285 (1999), pp. 221–227. 43. Q.-J. Li, A.R. Dinner, S. Qi, D.J. Irvine, J.B. Huppa, M.M. Davis and A.K. Chakraborty, CD4 enhances T-cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse, Nat. Immunol. 8 (2004), pp. 791–799. 44. H.Y. Liu, M. Rhodes, D.L. Wiest and D.A.A. Vignali, On the dynamics of TCR:CD3 complex cell surface expression and downmodulation, Immunity 13 (2000), pp. 665–675. 45. V. Das, B. Nal, A. Dujeancourt, M.I. Thoulouze, T. Galli, P. Roux, A. Dautry-Varsat and A. Alcover, Activation-induced polarized recycling targets T-cell antigen receptors to the immunological synapse: involvement of SNARE complexes, Immunity 20 (2004), pp. 577–588. 46. J. Sousa and J. Carneiro, A mathematical analysis of TCR serial triggering and down-regulation, Eur. J. Immunol. 30 (2000), pp. 3219–3227. 47. B.A. Lollo, K.W.H. Chan, E.M. Hanson, V.T. Moy and A.A. Brian, Direct evidence for two affinity states for lymphocyte function-associated antigen 1 on activated T cells, J. Biol. Chem. 268 (1993), pp. 21693–21700. 48. D.S. Lyons, S.A. Lieberman, J. Hampl, J. Boniface, Y. Chien, L.J. Berg and M.M. Davis, A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists, Immunity 5 (1996), pp. 53–61. 49. G.J. Kersh, M.J. Miley, C.A. Nelson, A. Grakoui, S. Horvath, D.L. Donermeyer, J. Kappler, P.M. Allen and D.H. Fremont, Structural and functional consequences of altering a peptide MHC anchor residue, J. Immunol. 166 (1998), pp. 3345–3354. 50. M. Krogsgaard, Q.J. Li, C. Sumen, J.B. Huppa, M. Huse and M.M. Davis, Agonist/endogenous peptide-MHC heterodimers drive T-cell activation and sensitivity, Nature 434 (2005), pp. 238–243. 51. C. Randriamampita and A. Trautmann, Ca2+ signals and T lymphocytes “new mechanisms and functions in Ca2+ signalling”, Biol. Cell 96 (2004), pp. 69–78. 52. S. Valitutti, S. Muller, M. Dessing and A. Lanzavecchi, Signal extinction and T-cell repolarization in T helper cell-antigen-presenting cell conjugates, Eur. J. Immunol. 26 (1996), pp. 2012–2016. 53. J. van Bergen, Y. Kooy and F. Koning, CD4-independent T cells impair TCR triggering of CD4-dependent T cells: a putative mechanism for T-cell affinity maturation, Eur. J. Immunol. 31 (2001), pp. 646–652. 54. W. Dummer, B. Ernst, E. LeRoy, D.-S. Lee and C.D. Surh, Autologous regulation of naive T-cell homeostasis within the T-cell compartment, J. Immunol. 166 (2001), pp. 2460–2468. 55. K.S. Schluns, W.C. Kieper, S.C. Jameson and L. Lefrancois, Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo, Nat. Immunol. 1 (2000), pp. 426–432. 56. R.M. Kedl, W.A. Rees, D.A. Hildeman, B.C. Schaefer, T. Mitchell, J.W. Kappler and P. Marrack, T cells compete for access to antigen-bearing antigen-presenting cells, J. Exp. Med. 192 (2000), pp. 1105–1113. 57. W. Rees, J. Bender, T.K. Teague, R.M. Kedl, F. Crawford, P. Marrack and J. Kappler, An inverse relationship between T-cell receptor affinity and antigen dose during CD4+ T-cell responses in vivo and in vitro, Proc. Natl. Acad. Sci. USA 96 (1999), pp. 9781–9786. 58. W. Yang and H.M. Grey, Study of the mechanism of TCR antagonism using dual-TCR-expressing T cells, J. Immunol. 170 (2003), pp. 4532–4538. 59. C. Wofsy, D. Coombs and B. Goldstein, Calculations show substantial serial engagement of T-cell receptors, Biophys. J. 80 (2001), pp. 606–612. 60. M.L. Dustin, D.E. Golan, D.M. Zhu, J.M. Miller, W. Meier, E.A. Davies and P.A. van der Merwe, Low affinity interaction of human or rat T-cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity, J. Biol. Chem. 272 (1997), pp. 30889–30898.
URI:	http://wrap.warwick.ac.uk/id/eprint/921