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Philos Trans R Soc Lond B Biol Sci. 2000 August 29; 355(1400): 1071–1076.
PMCID: PMC1692810

Thirty-six views of T-cell recognition.


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.
  • Boniface JJ, Reich Z, Lyons DS, Davis MM. 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. [PubMed]
  • Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC. 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. [PubMed]
  • Davis MM, Boniface JJ, 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. [PubMed]
  • Dustin ML, Olszowy MW, Holdorf AD, Li J, Bromley S, Desai N, Widder P, Rosenberger F, van der Merwe PA, Allen PM, et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell. 1998 Sep 4;94(5):667–677. [PubMed]
  • Garcia KC, Scott CA, Brunmark A, Carbone FR, Peterson PA, Wilson IA, Teyton L. CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes. Nature. 1996 Dec 12;384(6609):577–581. [PubMed]
  • Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999 Jul 9;285(5425):221–227. [PubMed]
  • Irving BA, 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. [PubMed]
  • Janeway CA., 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. [PubMed]
  • MILLER JF. Immunological function of the thymus. Lancet. 1961 Sep 30;2(7205):748–749. [PubMed]
  • Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature. 1998 Sep 3;395(6697):82–86. [PubMed]
  • Nicholson MW, Barclay AN, Singer MS, Rosen SD, van der Merwe PA. 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. [PubMed]
  • Redpath S, Alam SM, Lin CM, O'Rourke AM, Gascoigne NR. 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]
  • Reich Z, Boniface JJ, Lyons DS, Borochov N, Wachtel EJ, Davis MM. Ligand-specific oligomerization of T-cell receptor molecules. Nature. 1997 Jun 5;387(6633):617–620. [PubMed]
  • Savage PA, Boniface JJ, Davis MM. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999 Apr;10(4):485–492. [PubMed]
  • Tsien RY. The green fluorescent protein. Annu Rev Biochem. 1998;67:509–544. [PubMed]
  • van der Merwe PA, Brown MH, Davis SJ, Barclay AN. 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. [PubMed]
  • van der Merwe PA, Barclay AN, Mason DW, Davies EA, Morgan BP, Tone M, Krishnam AK, Ianelli C, Davis SJ. 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. [PubMed]
  • van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Willcox BE, Gao GF, Wyer JR, Ladbury JE, Bell JI, Jakobsen BK, van der Merwe PA. TCR binding to peptide-MHC stabilizes a flexible recognition interface. Immunity. 1999 Mar;10(3):357–365. [PubMed]
  • Wülfing C, Davis MM. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science. 1998 Dec 18;282(5397):2266–2269. [PubMed]
  • Wülfing C, Sjaastad MD, Davis MM. 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. [PubMed]

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