Thirty-six views of T-cell recognition

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 09/2000; 355(1400):1071-6. DOI: 10.1098/rstb.2000.0644
Source: PubMed


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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    • "In contrast, work focused on understanding the biophysical parameters of MHC–TCR binding that correlate with triggering has questioned long standing paradigms previously held. Initial measurements of MHC–TCR binding, have correlated slower off-rates of binding (or long half-life of interaction) with better T cell activation (51), with antagonists, in general, having intermediate off-rates compared to agonists and null peptides (52). These measurements were conducted in solution in 3D, with all forms of motion for both molecules in play. "
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    • "Interestingly , the specific triggering rate w ij is maximal at an intermediate dissociation time on the order of T R ( Fig . 1 ) ; cf . Kalergis et al . ( 2001 ) ; Krummel et al . ( 2000 ) ; Lanzavecchia et al . ( 1999 ) . A pMHC j for which w ij achieves its maximum value is called an optimal agonist ."
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    ABSTRACT: We consider the way in which antigen is presented to T cells on MHC molecules and ask how MHC peptide presentation could be optimized so as to obtain an effective and safe immune response. By analysing this problem with a mathematical model of T-cell activation, we deduce the need for both MHC restriction and high presentation selectivity. We find that the optimal selectivity is such that about one pathogen-derived peptide is presented per MHC isoform, on the average. We also indicate upper and lower bounds to the number of MHC isoforms per individual based on detectability requirements. Thus we deduce that an important role of MHC presentation is to act as a filter that limits the diversity of antigen presentation.
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