Mechanisms for T cell receptor triggering (original) (raw)
Related papers
Interactions of TCRs with MHC-peptide complexes: a quantitative basis for mechanistic models
Current Opinion in Immunology, 1997
The activation of T lymphocytes is initiated by the binding of MHC-peptide complexes on antigen-presenting cells to MHC-restricted, peptide specific TCRs. Significant progress has recently been made in understanding the structure of the TCR and in the direct quantitative examination of the primary binding interactions between MHC-peptide complexes and the TCR. Attempts to develop quantitative models for the differential activation of T cells by MHC-peptide ligands that differ subtly in their structure have largely been based on either the affinity of the MHC-peptide complexe s for the TCR in question or on the dissociation kinetics of the MHC-peptide complex from the T cell.
Journal of immunology (Baltimore, Md. : 1950), 1999
In the present study, we examined the relationships among quantitative aspects of TCR engagement as measured by receptor down-modulation, functional responses, and biochemical signaling events using both mouse and human T cell clones. For T cells from both species, ligands that are more potent in inducing functional responses promote TCR down-modulation more efficiently than weaker ligands. At low ligand density, the number of down-modulated TCR exceeds the number of available ligands by as much as 80-100:1 in the optimal human case, confirming the previous description of serial ligand engagement of TCR (Valitutti, et al. 1995. Nature 375:148-151). A previously unappreciated relationship involving TCR down-modulation, the pattern of proximal TCR signaling, and the extent of serial engagement was revealed by analyzing different ligands for the same TCR. Functionally, more potent ligands induce a higher proportion of fully tyrosine phosphorylated zeta-chains and a greater amount of ph...
T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity
Science, 1995
The critical discriminatory event in the activation of T lymphocytes bearing UP T cell receptors (TCRs) is their interaction with a molecular complex consisting of a peptide bound to a major histocompatibility complex (MHC)-encoded class or class 11 molecule on the surface of an antigen-presenting cell. The kinetics of binding were measured of a purified TCR to molecular complexes of a purified soluble analog of the murine MHC class molecule H-2Ld (sH-2Ld) and a synthetic octamer peptide p2CL in a direct, real-time assay based on surface plasmon resonance. The kinetic dissociation rate of the MHCpeptide complex from the TCR was rapid (2.6 x 10-2 second-1, corresponding to a half-time for dissociation of approximately 27 seconds), and the kinetic association rate was 2.1 x 105 M-1 second-'. The equilibrium constant for dissociation was approximately 10-7 M. These values indicate that TCRs must interact with a multivalent array of MHC-peptide complexes to trigger T cell signaling.
The Journal of Immunology, 2000
The TCR recognition of peptides bound to MHC class II molecules is highly flexible in some T cells. Although progress has been made in understanding the interactions within the trimolecular complex, to what extent the individual components and their amino acid composition contribute to ligand recognition by individual T cells is not completely understood. We investigated how single amino acid residues influence Ag recognition of T cells by combining several experimental approaches. We defined TCR motifs for CD4 ؉ T cells using peptide synthetic combinatorial libraries in the positional scanning format (PS-SCL) and single amino acid-modified peptide analogues. The similarity of the TCR motifs defined by both methods and the identification of stimulatory antigenic peptides by the PS-SCL approach argue for a contribution of each amino acid residue to the overall potency of the antigenic peptide ligand. In some instances, however, motifs are formed by adjacent amino acids, and their combined influence is superimposed on the overall contribution of each amino acid within the peptide epitope. In contrast to the flexibility of the TCR to interact with different peptides, recognition was very sensitive toward modifications of the MHC-restriction element. Exchanges of just one amino acid of the MHC molecule drastically reduced the number of peptides recognized. The results indicate that a specific MHC molecule not only selects certain peptides, but also is crucial for setting an affinity threshold for TCR recognition, which determines the flexibility in peptide recognition for a given TCR. The Journal of Immunology, 2000, 164: 861-871. C D4 ϩ T cells recognize short peptides bound to MHC class II molecules. This interaction was initially considered highly specific and limited to a few peptides with similar or closely related sequences. Recent observations have challenged this view and demonstrated that recognition of MHCpeptide complexes by the TCR is highly flexible (1, 2). Accordingly, it is assumed that degeneracy in Ag recognition is important for thymic selection of the T cell repertoire, since a broad spectrum of T cell specificities can be selected on a limited number of self-MHC-self-peptide complexes (3). It is also possible that flexibility of the TCR is crucial for peripheral survival of mature T cells. The observation that T cells require a continuous signal through their Ag receptor to stay alive (4) has promoted the idea that individual TCRs may interact with a wide range of self-MHC-self-peptide complexes and that the latter provide a survival signal. Therefore, positive selection in the thymus and survival of T cells in the periphery may be the result of low-affinity interactions of the TCR with self-MHC-self-peptide complexes on the basis of degenerate T cell recognition (1, 2). Although low potency stimulation may serve to support survival of peripheral T cells, high potency ligands permit full agonist responses at low Ag concentrations, e.g., during immune responses against invading pathogens.
T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand
Nature, 2005
The binding of a T-cell antigen receptor (TCR) to peptide antigen presented by major histocompatibility antigens (pMHC) on antigen-presenting cells (APCs) is a central event in adaptive immune responses 1,2 . The mechanism by which TCR-pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial 3-5 . It has been proposed 6-8 that TCR triggering is promoted by segregation at the T cell-APC interface of cell-surface molecules with small ectodomains (such as TCR-pMHC and accessory receptors) from molecules with large ectodomains (such as the receptor protein tyrosine phosphatases CD45 and CD148). Here we show that increasing the dimensions of the TCR-pMHC interaction by elongating the pMHC ectodomain greatly reduces TCR triggering without affecting TCR-pMHC ligation. A similar dependence on receptor-ligand complex dimensions was observed with artificial TCR-ligand systems that span the same dimensions as the TCR-pMHC complex. Interfaces between T cells and APCs expressing elongated pMHC showed an increased intermembrane separation distance and less depletion of CD45. These results show the importance of the small size of the TCR-pMHC complex and support a role for sizebased segregation of cell-surface molecules in TCR triggering.
T Cell Receptor Binding Transition States and Recognition of Peptide/MHC
Biochemistry, 2007
T cell receptor recognition of peptide/MHC has been described as proceeding through a "twostep" process in which the TCR first contacts the MHC molecule prior to formation of the binding transition state using the germline-encoded CDR1 and CDR2 loops. The receptor then contacts the peptide using the hypervariable CDR3 loops as the transition state decays to the bound state. The model subdivides TCR binding into peptide-independent and peptide-dependent steps, demarcated at the binding transition state. Investigating the two-step model, here we show that two TCRs that recognize the same peptide/ MHC bury very similar amounts of solvent-accessible surface area in their transition states. However, 1300-1500 Å 2 of surface area is buried in each, a significant amount suggestive of participation of peptide and associated CDR3 surface. Consistent with this interpretation, analysis of peptide and TCR variants indicates that stabilizing contacts to the peptide are formed within both transition states. These data are incompatible with the original two-step model, as are transition state models built using the principle of minimal frustration commonly employed in the investigation of protein folding and binding transition states. These findings will be useful in further explorations of the nature of TCR binding transition states, as well as ongoing efforts to understand the mechanisms by which T cell receptors recognize the composite peptide/MHC surface.
The Journal of Immunology
We describe a comprehensive analysis of the effect of avidity of TCR-MHC/peptide interaction on activation of the (p2Ca). In study, monosubstituted variants of p2Ca were used and assessed for binding to purified H-2Ld, binding of H-2Ld/peptide complexes to sTCR, and ability to activate 2C cells to two independent effector functions. Among the > 20 variants analyzed, functional activity of most peptides that bound the MHC well correlated with the strength of interaction of MHC/peptide complexes with sTCR. However, with some variants, a clear discordance between the apparent TCR-MHC/peptide affinity and biologic function was observed, demonstrating that the former cannot always be gauged by the latter. In the case of L4 peptide (phenylalanine at position 4 substituted with leucine), peptide/MHC complexes showed no detectable binding to sTCR, indicating a 10-fold or greater decrease in affinity. Nevertheless, this peptide sensitized target cells for lysis at a level equivalent to th...
Journal of Biological Chemistry, 2014
Background: TCR recognition of bipartite ligands composed of self (MHC) and non-self (peptide) maintains T-cell specificity. Results: Mutation of residues in the cognate peptide override TCR mutations that enhance MHC binding. Conclusion: TCR-pMHC binding affinity requires specific TCR-peptide interactions. Significance: Stabilization of TCR-pMHC engagement by TCR-peptide interactions maintains T-cell specificity and prevents recognition of self-pMHC in the periphery. ␣ T-cell receptors (TCRs) engage antigens using complementarity-determining region (CDR) loops that are either germ line-encoded (CDR1 and CDR2) or somatically rearranged (CDR3). TCR ligands compose a presentation platform (major histocompatibility complex (MHC)) and a variable antigenic component consisting of a short "foreign" peptide. The sequence of events when the TCR engages its peptide-MHC (pMHC) ligand remains unclear. Some studies suggest that the germ line elements of the TCR engage the MHC prior to peptide scanning, but this order of binding is difficult to reconcile with some TCR-pMHC structures. Here, we used TCRs that exhibited enhanced pMHC binding as a result of mutations in either CDR2 and/or CDR3 loops, that bound to the MHC or peptide, respectively, to dissect the roles of these loops in stabilizing TCR-pMHC interactions. Our data show that TCR-peptide interactions play a strongly dominant energetic role providing a binding mode that is both temporally and energetically complementary with a system requiring positive selection by self-pMHC in the thymus and rapid recognition of non-self-pMHC in the periphery.
TCR Binding to Peptide-MHC Stabilizes a Flexible Recognition Interface
Immunity, 1999
This raises the question as to how TCRs achieve Institute of Molecular Medicine this level of cross-reactivity. John Radcliffe Hospital As with conventional cell-cell recognition molecules Oxford, OX3 9DS (van der Merwe and Barclay, 1994; Davis et al., 1998b), † Department of Biochemistry and Molecular Biology TCR/peptide-MHC interactions have a low affinity (Kd University College London 1-90 M) (Davis et al., 1998a). However, in contrast to London, WC1E 6BT other cell-cell recognition molecules, in which the low ‡ Sir William Dunn School of Pathology affinity is a consequence of a fast dissociation rate con-University of Oxford stant (k off ) (van der Merwe and Barclay, 1994; Davis et Oxford, OX1 3RE al., 1998b), the low affinity of TCR/peptide-MHC interac-United Kingdom tions is also a consequence of slow association rate constants (k on ) (Davis et al., 1998a). The k on values (10 2 -10 4 M Ϫ1 ϫ s Ϫ1 ) reported for TCR/peptide-MHC interac-Summary tions are up to three orders of magnitude slower than those measured for other cell-cell recognition mole-The binding of TCRs to their peptide-MHC ligands is cules (van der Merwe et al., 1994; Davis et al., 1998a, characterized by a low affinity, slow kinetics, and a 1998b). Similarly, reported k off values (10 Ϫ2 -10 Ϫ1 s Ϫ1 ), high degree of cross-reactivity. Here, we report the although fast when compared with high-affinity proteinresults of a kinetic and thermodynamic analysis of protein interactions (Ͻ10 Ϫ3 s Ϫ1 ), are much slower than two TCRs binding to their peptide-MHC ligands, which protein-protein interactions with equivalent affinities reveal two striking features. First, significant activa-(Ͼ1 s Ϫ1 ) (van der Merwe et al., 1994; Davis et al., 1998a, tion energy barriers must be overcome during both 1998b)
The Journal of Immunology, 2003
The interaction between TCR and peptide-MHC (pMHC) complexes is crucial for the activation of T cells as well as for positive and negative selection in the thymus. The kinetics and affinity of this interaction and the densities of TCR and pMHC complexes on the cell surface are determining factors for different outcomes during thymic selection. In general, it is thought that agonist pMHC, which cause negative selection, have higher affinities and, in particular, slower off-rates than partial or weak agonists and antagonists, which cause positive selection. In this study, we have used pMHC tetramers to investigate the kinetics of TCR-pMHC interaction for agonist, weak agonist, and antagonist ligands of the anti-lymphocytic choriomeningitis virus P14 TCR. Kinetics determined on the cell surface may be biologically more relevant than methods using soluble proteins. We can distinguish between agonists and weak agonists or antagonists based on the half-life and the avidity of tetramer-TCR interaction. Furthermore, we show that a weak agonist self-peptide that positively selects P14 TCR ؉ thymocytes has a tetramer half-life and avidity only slightly weaker than strong agonists. We show that, in fact, it can act as quite a strong agonist, but that its poor ability to stabilize MHC causes it instead to have a weak agonist phenotype.