Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2001 Nov;81(5):2547–2557. doi: 10.1016/S0006-3495(01)75899-7

T-cell activation by soluble MHC oligomers can be described by a two-parameter binding model.

J D Stone 1, J R Cochran 1, L J Stern 1
PMCID: PMC1301723  PMID: 11606269

Abstract

T-cell activation is essential for initiation and control of immune system function. T cells are activated by interaction of cell-surface antigen receptors with major histocompatibility complex (MHC) proteins on the surface of other cells. Studies using soluble oligomers of MHC-peptide complexes and other types of receptor cross-linking agents have supported an activation mechanism that involves T cell receptor clustering. Receptor clustering induced by incubation of T cells with MHC-peptide oligomers leads to the induction of T-cell activation processes, including downregulation of engaged receptors and upregulation of the cell-surface proteins CD69 and CD25. Dose-response curves for these T-cell activation markers are bell-shaped, with different maxima and midpoints, depending on the valency of the soluble oligomer used. In this study, we have analyzed the activation behavior using a mathematical model that describes the binding of multivalent ligands to cell-surface receptors. We show that a simple equilibrium binding model accurately describes the activation data for CD4(+) T cells treated with MHC-peptide oligomers of varying valency. The model can be used to predict activation and binding behavior for T cells and MHC oligomers with different properties.

Full Text

The Full Text of this article is available as a PDF (248.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abastado J. P., Lone Y. C., Casrouge A., Boulot G., Kourilsky P. Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T cell hybridoma and induction of unresponsiveness. J Exp Med. 1995 Aug 1;182(2):439–447. doi: 10.1084/jem.182.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aivazian D., Stern L. J. Phosphorylation of T cell receptor zeta is regulated by a lipid dependent folding transition. Nat Struct Biol. 2000 Nov;7(11):1023–1026. doi: 10.1038/80930. [DOI] [PubMed] [Google Scholar]
  3. Anton van der Merwe P., Davis S. J., Shaw A. S., Dustin M. L. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin Immunol. 2000 Feb;12(1):5–21. doi: 10.1006/smim.2000.0203. [DOI] [PubMed] [Google Scholar]
  4. Appel H., Gauthier L., Pyrdol J., Wucherpfennig K. W. Kinetics of T-cell receptor binding by bivalent HLA-DR. Peptide complexes that activate antigen-specific human T-cells. J Biol Chem. 2000 Jan 7;275(1):312–321. doi: 10.1074/jbc.275.1.312. [DOI] [PubMed] [Google Scholar]
  5. Boniface J. J., Rabinowitz J. D., Wülfing C., Hampl J., Reich Z., Altman J. D., Kantor R. M., Beeson C., McConnell H. M., Davis M. M. Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected]. Immunity. 1998 Oct;9(4):459–466. doi: 10.1016/s1074-7613(00)80629-9. [DOI] [PubMed] [Google Scholar]
  6. Bray D., Levin M. D., Morton-Firth C. J. Receptor clustering as a cellular mechanism to control sensitivity. Nature. 1998 May 7;393(6680):85–88. doi: 10.1038/30018. [DOI] [PubMed] [Google Scholar]
  7. Cameron T. O., Cochran J. R., Yassine-Diab B., Sékaly R. P., Stern L. J. Cutting edge: detection of antigen-specific CD4+ T cells by HLA-DR1 oligomers is dependent on the T cell activation state. J Immunol. 2001 Jan 15;166(2):741–745. doi: 10.4049/jimmunol.166.2.741. [DOI] [PubMed] [Google Scholar]
  8. Cantrell D. T cell antigen receptor signal transduction pathways. Annu Rev Immunol. 1996;14:259–274. doi: 10.1146/annurev.immunol.14.1.259. [DOI] [PubMed] [Google Scholar]
  9. Casares S., Zong C. S., Radu D. L., Miller A., Bona C. A., Brumeanu T. D. Antigen-specific signaling by a soluble, dimeric peptide/major histocompatibility complex class II/Fc chimera leading to T helper cell type 2 differentiation. J Exp Med. 1999 Aug 16;190(4):543–553. doi: 10.1084/jem.190.4.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chambers C. A. The expanding world of co-stimulation: the two-signal model revisited. Trends Immunol. 2001 Apr;22(4):217–223. doi: 10.1016/s1471-4906(01)01868-3. [DOI] [PubMed] [Google Scholar]
  11. Chan A. C., Desai D. M., Weiss A. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu Rev Immunol. 1994;12:555–592. doi: 10.1146/annurev.iy.12.040194.003011. [DOI] [PubMed] [Google Scholar]
  12. Chicz R. M., Urban R. G., Lane W. S., Gorga J. C., Stern L. J., Vignali D. A., Strominger J. L. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature. 1992 Aug 27;358(6389):764–768. doi: 10.1038/358764a0. [DOI] [PubMed] [Google Scholar]
  13. Cochran J. R., Aivazian D., Cameron T. O., Stern L. J. Receptor clustering and transmembrane signaling in T cells. Trends Biochem Sci. 2001 May;26(5):304–310. doi: 10.1016/s0968-0004(01)01815-1. [DOI] [PubMed] [Google Scholar]
  14. Cochran J. R., Cameron T. O., Stern L. J. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Immunity. 2000 Mar;12(3):241–250. doi: 10.1016/s1074-7613(00)80177-6. [DOI] [PubMed] [Google Scholar]
  15. Cochran J. R., Cameron T. O., Stone J. D., Lubetsky J. B., Stern L. J. Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation. J Biol Chem. 2001 May 30;276(30):28068–28074. doi: 10.1074/jbc.M103280200. [DOI] [PubMed] [Google Scholar]
  16. Cochran J. R., Stern L. J. A diverse set of oligomeric class II MHC-peptide complexes for probing T-cell receptor interactions. Chem Biol. 2000 Sep;7(9):683–696. doi: 10.1016/s1074-5521(00)00019-3. [DOI] [PubMed] [Google Scholar]
  17. Crawford F., Kozono H., White J., Marrack P., Kappler J. Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity. 1998 Jun;8(6):675–682. doi: 10.1016/s1074-7613(00)80572-5. [DOI] [PubMed] [Google Scholar]
  18. Davis M. M., Boniface J. J., Reich Z., Lyons D., Hampl J., Arden B., Chien Y. Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol. 1998;16:523–544. doi: 10.1146/annurev.immunol.16.1.523. [DOI] [PubMed] [Google Scholar]
  19. DeLisi C., Chabay R. The influence of cell surface receptor clustering on the thermodynamics of ligand binding and the kinetics of its dissociation. Cell Biophys. 1979 Jun;1(2):117–131. [PubMed] [Google Scholar]
  20. Delisi C., Siraganian R. P. Receptor cross-linking and histamine release. II. Interpretation and analysis of anomalous dose response patterns. J Immunol. 1979 Jun;122(6):2293–2299. [PubMed] [Google Scholar]
  21. Fahmy T. M., Bieler J. G., Edidin M., Schneck J. P. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity. 2001 Feb;14(2):135–143. [PubMed] [Google Scholar]
  22. Ferlin W., Glaichenhaus N., Mougneau E. Present difficulties and future promise of MHC multimers in autoimmune exploration. Curr Opin Immunol. 2000 Dec;12(6):670–675. doi: 10.1016/s0952-7915(00)00161-8. [DOI] [PubMed] [Google Scholar]
  23. Fernández-Miguel G., Alarcón B., Iglesias A., Bluethmann H., Alvarez-Mon M., Sanz E., de la Hera A. Multivalent structure of an alphabetaT cell receptor. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1547–1552. doi: 10.1073/pnas.96.4.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Frayser M., Sato A. K., Xu L., Stern L. J. Empty and peptide-loaded class II major histocompatibility complex proteins produced by expression in Escherichia coli and folding in vitro. Protein Expr Purif. 1999 Feb;15(1):105–114. doi: 10.1006/prep.1998.0987. [DOI] [PubMed] [Google Scholar]
  25. Germain R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994 Jan 28;76(2):287–299. doi: 10.1016/0092-8674(94)90336-0. [DOI] [PubMed] [Google Scholar]
  26. Germain R. N. T-cell signaling: the importance of receptor clustering. Curr Biol. 1997 Oct 1;7(10):R640–R644. doi: 10.1016/s0960-9822(06)00323-x. [DOI] [PubMed] [Google Scholar]
  27. Hamad A. R., O'Herrin S. M., Lebowitz M. S., Srikrishnan A., Bieler J., Schneck J., Pardoll D. Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor. J Exp Med. 1998 Nov 2;188(9):1633–1640. doi: 10.1084/jem.188.9.1633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hlavacek W. S., Perelson A. S., Sulzer B., Bold J., Paar J., Gorman W., Posner R. G. Quantifying aggregation of IgE-FcepsilonRI by multivalent antigen. Biophys J. 1999 May;76(5):2421–2431. doi: 10.1016/s0006-3495(99)77397-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Irving B. A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. doi: 10.1016/0092-8674(91)90314-o. [DOI] [PubMed] [Google Scholar]
  30. Itoh Y., Germain R. N. Single cell analysis reveals regulated hierarchical T cell antigen receptor signaling thresholds and intraclonal heterogeneity for individual cytokine responses of CD4+ T cells. J Exp Med. 1997 Aug 29;186(5):757–766. doi: 10.1084/jem.186.5.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Janeway C. A., Jr Ligands for the T-cell receptor: hard times for avidity models. Immunol Today. 1995 May;16(5):223–225. doi: 10.1016/0167-5699(95)80163-4. [DOI] [PubMed] [Google Scholar]
  32. Lamb J. R., Eckels D. D., Lake P., Woody J. N., Green N. Human T-cell clones recognize chemically synthesized peptides of influenza haemagglutinin. Nature. 1982 Nov 4;300(5887):66–69. doi: 10.1038/300066a0. [DOI] [PubMed] [Google Scholar]
  33. Letourneur F., Klausner R. D. T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8905–8909. doi: 10.1073/pnas.88.20.8905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Liu H., Rhodes M., Wiest D. L., Vignali D. A. On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity. 2000 Nov;13(5):665–675. doi: 10.1016/s1074-7613(00)00066-2. [DOI] [PubMed] [Google Scholar]
  35. Matsui K., Boniface J. J., Steffner P., Reay P. A., Davis M. M. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12862–12866. doi: 10.1073/pnas.91.26.12862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. McMichael A. J., O'Callaghan C. A. A new look at T cells. J Exp Med. 1998 May 4;187(9):1367–1371. doi: 10.1084/jem.187.9.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Qian D., Weiss A. T cell antigen receptor signal transduction. Curr Opin Cell Biol. 1997 Apr;9(2):205–212. doi: 10.1016/s0955-0674(97)80064-6. [DOI] [PubMed] [Google Scholar]
  38. Reichstetter S., Ettinger R. A., Liu A. W., Gebe J. A., Nepom G. T., Kwok W. W. Distinct T cell interactions with HLA class II tetramers characterize a spectrum of TCR affinities in the human antigen-specific T cell response. J Immunol. 2000 Dec 15;165(12):6994–6998. doi: 10.4049/jimmunol.165.12.6994. [DOI] [PubMed] [Google Scholar]
  39. Schwartz R. H. T cell clonal anergy. Curr Opin Immunol. 1997 Jun;9(3):351–357. doi: 10.1016/s0952-7915(97)80081-7. [DOI] [PubMed] [Google Scholar]
  40. Sette A., Alexander J., Ruppert J., Snoke K., Franco A., Ishioka G., Grey H. M. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol. 1994;12:413–431. doi: 10.1146/annurev.iy.12.040194.002213. [DOI] [PubMed] [Google Scholar]
  41. Shaw A. S., Dustin M. L. Making the T cell receptor go the distance: a topological view of T cell activation. Immunity. 1997 Apr;6(4):361–369. doi: 10.1016/s1074-7613(00)80279-4. [DOI] [PubMed] [Google Scholar]
  42. Testi R., D'Ambrosio D., De Maria R., Santoni A. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol Today. 1994 Oct;15(10):479–483. doi: 10.1016/0167-5699(94)90193-7. [DOI] [PubMed] [Google Scholar]
  43. Valitutti S., Müller S., Salio M., Lanzavecchia A. Degradation of T cell receptor (TCR)-CD3-zeta complexes after antigenic stimulation. J Exp Med. 1997 May 19;185(10):1859–1864. doi: 10.1084/jem.185.10.1859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Viola A., Schroeder S., Sakakibara Y., Lanzavecchia A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science. 1999 Jan 29;283(5402):680–682. doi: 10.1126/science.283.5402.680. [DOI] [PubMed] [Google Scholar]
  45. Waldmann T. A. The multi-subunit interleukin-2 receptor. Annu Rev Biochem. 1989;58:875–911. doi: 10.1146/annurev.bi.58.070189.004303. [DOI] [PubMed] [Google Scholar]
  46. Wickham T. J., Granados R. R., Wood H. A., Hammer D. A., Shuler M. L. General analysis of receptor-mediated viral attachment to cell surfaces. Biophys J. 1990 Dec;58(6):1501–1516. doi: 10.1016/S0006-3495(90)82495-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Xavier R., Seed B. Membrane compartmentation and the response to antigen. Curr Opin Immunol. 1999 Jun;11(3):265–269. doi: 10.1016/s0952-7915(99)80043-0. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES