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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2000 Aug 29;355(1400):1071–1076. doi: 10.1098/rstb.2000.0644

Thirty-six views of T-cell recognition.

M Krummel 1, C Wülfing 1, C Sumen 1, M M Davis 1
PMCID: PMC1692810  PMID: 11186308

Abstract

While much is known about the signalling pathways within lymphocytes that are triggered during activation, much less is known about how the various cell surface molecules on T cells initiate these events. To address this, we have focused on the primary interaction that drives T-cell activation, namely the binding of a particular T-cell receptor (TCR) to peptide-MHC ligands, and find a close correlation between biological activity and off-rate; that is, the most stimulatory TCR ligands have the slowest dissociation rates. In general, TCRs from multiple histocompatibility complex (MHC) class-II-restricted T cells have half-lives of 1-11s at 25 degrees C, a much narrower range than found with antibodies and suggesting a strong selection for an optimum dissociation rate. TCR ligands with even faster dissociation rates tend to be antagonists. To observe the effects of these different ligands in their physiological setting, we made gene fusions of various molecules with green fluorescent protein (GFP), transfected them into the relevant lymphocytes, and observed their movements during T-cell recognition using multicolour video microscopy. We find that clustering of CD3zeta-GFP and CD4-GFP on the Tcell occurs concomitantly or slightly before the first rise in calcium by the T cell, and that various GFP-labelled molecules on the B-cell side cluster shortly thereafter (ICAM-1, class II MHC, CD48), apparently driven byT-cell molecules. Most of this movement towards the interface is mediated by signals through the co-stimulatory receptors, CD28 and LFA-1, and involves myosin motors and the cortical actin cytoskeleton. Thus, we have proposed that the principal mechanism by which co-stimulation enhances T-cell responsiveness is by increasing the local density of T-cell activation molecules, their ligands and their attendant signalling apparatus. In collaboration with Michael Dustin and colleagues, we have also found that the formation and stability of the TCR-peptide-MHC cluster at the centre of the interaction cap between T and B cells is highly dependent on the dissociation rate of the TCR and its ligand. Thus, we are able to link this kinetic parameter to the formation of a cell surface structure that is linked to and probably causal with respect to T-cell activation.

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Selected References

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

  1. Boniface J. J., Reich Z., Lyons D. S., Davis M. M. Thermodynamics of T cell receptor binding to peptide-MHC: evidence for a general mechanism of molecular scanning. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11446–11451. doi: 10.1073/pnas.96.20.11446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cornall R. J., Cyster J. G., Hibbs M. L., Dunn A. R., Otipoby K. L., Clark E. A., Goodnow C. C. Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity. 1998 Apr;8(4):497–508. doi: 10.1016/s1074-7613(00)80554-3. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Dustin M. L., Olszowy M. W., Holdorf A. D., Li J., Bromley S., Desai N., Widder P., Rosenberger F., van der Merwe P. A., Allen P. M. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell. 1998 Sep 4;94(5):667–677. doi: 10.1016/s0092-8674(00)81608-6. [DOI] [PubMed] [Google Scholar]
  5. Garcia K. C., Scott C. A., Brunmark A., Carbone F. R., Peterson P. A., Wilson I. A., Teyton L. CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes. Nature. 1996 Dec 12;384(6609):577–581. doi: 10.1038/384577a0. [DOI] [PubMed] [Google Scholar]
  6. Grakoui A., Bromley S. K., Sumen C., Davis M. M., Shaw A. S., Allen P. M., Dustin M. L. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999 Jul 9;285(5425):221–227. doi: 10.1126/science.285.5425.221. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Janeway C. A., Jr The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol. 1992;10:645–674. doi: 10.1146/annurev.iy.10.040192.003241. [DOI] [PubMed] [Google Scholar]
  9. MILLER J. F. Immunological function of the thymus. Lancet. 1961 Sep 30;2(7205):748–749. doi: 10.1016/s0140-6736(61)90693-6. [DOI] [PubMed] [Google Scholar]
  10. Monks C. R., Freiberg B. A., Kupfer H., Sciaky N., Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature. 1998 Sep 3;395(6697):82–86. doi: 10.1038/25764. [DOI] [PubMed] [Google Scholar]
  11. Nicholson M. W., Barclay A. N., Singer M. S., Rosen S. D., van der Merwe P. A. Affinity and kinetic analysis of L-selectin (CD62L) binding to glycosylation-dependent cell-adhesion molecule-1. J Biol Chem. 1998 Jan 9;273(2):763–770. doi: 10.1074/jbc.273.2.763. [DOI] [PubMed] [Google Scholar]
  12. Redpath S., Alam S. M., Lin C. M., O'Rourke A. M., Gascoigne N. R. Cutting edge: trimolecular interaction of TCR with MHC class II and bacterial superantigen shows a similar affinity to MHC:peptide ligands. J Immunol. 1999 Jul 1;163(1):6–10. [PubMed] [Google Scholar]
  13. Reich Z., Boniface J. J., Lyons D. S., Borochov N., Wachtel E. J., Davis M. M. Ligand-specific oligomerization of T-cell receptor molecules. Nature. 1997 Jun 5;387(6633):617–620. doi: 10.1038/42500. [DOI] [PubMed] [Google Scholar]
  14. Savage P. A., Boniface J. J., Davis M. M. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999 Apr;10(4):485–492. doi: 10.1016/s1074-7613(00)80048-5. [DOI] [PubMed] [Google Scholar]
  15. Tsien R. Y. The green fluorescent protein. Annu Rev Biochem. 1998;67:509–544. doi: 10.1146/annurev.biochem.67.1.509. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Willcox B. E., Gao G. F., Wyer J. R., Ladbury J. E., Bell J. I., Jakobsen B. K., van der Merwe P. A. TCR binding to peptide-MHC stabilizes a flexible recognition interface. Immunity. 1999 Mar;10(3):357–365. doi: 10.1016/s1074-7613(00)80035-7. [DOI] [PubMed] [Google Scholar]
  18. Wülfing C., Davis M. M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science. 1998 Dec 18;282(5397):2266–2269. doi: 10.1126/science.282.5397.2266. [DOI] [PubMed] [Google Scholar]
  19. Wülfing C., Sjaastad M. D., Davis M. M. Visualizing the dynamics of T cell activation: intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6302–6307. doi: 10.1073/pnas.95.11.6302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. van der Merwe P. A., Barclay A. N., Mason D. W., Davies E. A., Morgan B. P., Tone M., Krishnam A. K., Ianelli C., Davis S. J. Human cell-adhesion molecule CD2 binds CD58 (LFA-3) with a very low affinity and an extremely fast dissociation rate but does not bind CD48 or CD59. Biochemistry. 1994 Aug 23;33(33):10149–10160. doi: 10.1021/bi00199a043. [DOI] [PubMed] [Google Scholar]
  21. van der Merwe P. A., Bodian D. L., Daenke S., Linsley P., Davis S. J. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med. 1997 Feb 3;185(3):393–403. doi: 10.1084/jem.185.3.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. van der Merwe P. A., Brown M. H., Davis S. J., Barclay A. N. Affinity and kinetic analysis of the interaction of the cell adhesion molecules rat CD2 and CD48. EMBO J. 1993 Dec 15;12(13):4945–4954. doi: 10.1002/j.1460-2075.1993.tb06188.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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