Receptor pre-clustering and T cell responses: Insights into molecular mechanisms (original) (raw)
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Nature Immunology, 2001
Cytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide-major histocompatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). We examined the effect of mutations in the antigen-binding site of a K b -restricted TCR on T cell activation, antigen binding and dissociation from antigen.These parameters were also examined for variants derived from a K d -restricted peptide that was recognized by a CTL clone. Using these two independent systems, we show that T
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.
Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time
Immunity, 2010
T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1G4 TCR-pMHC binding properties measured in solution. We found that both the on rate (k on ) and off rate (k off ) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or "confinement time" of a TCR-pMHC interaction. This confinement time model clarifies the role of k on in T cell activation and reconciles apparently contradictory reports on the role of TCR-pMHC binding kinetics and affinity in T cell activation.
MHC binding affects the dynamics of different T-cell receptors in different ways
PLOS Computational Biology, 2019
T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of pMHC to the TCR initiates signalling within the T cell. One hypothesis is that conformational changes in the TCR lead to further downstream signalling. Here we investigate four different TCRs in their free state as well as in their pMHC bound state using large scale molecular simulations totalling 26 000 ns. We find that the dynamical features within TCRs differ significantly between unbound TCR and TCR/pMHC simulations. However, apart from expected results such as reduced solvent accessibility and flexibility of the interface residues, these features are not conserved among different TCR types. The presence of a pMHC alone is not sufficient to cause cross-TCR-conserved dynamical features within a TCR. Our results argue against models of TCR triggering involving conserved allosteric conformational changes.
The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness
Nature, 2010
The T-cell receptor (TCR) interacts with peptide-major histocompatibility complexes (pMHC) to discriminate pathogens from selfantigens and trigger adaptive immune responses. Direct physical contact is required between the T cell and the antigen-presenting cell for cross-junctional binding where the TCR and pMHC are anchored on two-dimensional (2D) membranes of the apposing cells 1 . Despite their 2D nature, TCR-pMHC binding kinetics have only been analysed three-dimensionally (3D) with a varying degree of correlation with the T-cell responsiveness 2-4 . Here we use two mechanical assays 5,6 to show high 2D affinities between a TCR and its antigenic pMHC driven by rapid on-rates. Compared to their 3D counterparts, 2D affinities and on-rates of the TCR for a panel of pMHC ligands possess far broader dynamic ranges that match that of their corresponding T-cell responses. The best 3D predictor of response is the off-rate, with agonist pMHC dissociating the slowest 2-4 . In contrast, 2D off-rates are up to 8,300-fold faster, with the agonist pMHC dissociating the fastest. Our 2D data suggest rapid antigen sampling by T cells and serial engagement of a few agonist pMHCs by TCRs in a large self pMHC background. Thus, the cellular environment amplifies the intrinsic TCR-pMHC binding to generate broad affinities and rapid kinetics that determine T-cell responsiveness.
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.
Predicting interactions between T cell receptors and MHC-peptide complexes
Molecular Immunology, 2011
Conserved interactions between T cell receptors (TCRs) and major histocompatibility complex (MHC) proteins with bound peptide antigens are not well understood. In order to gain a better understanding of the interaction modes of human TCR variable (V) regions, we have performed a structural analysis of the TCRs bound to their MHC-peptide ligands in human, using the available structural models determined by X-ray crystallography. We identified important differences to previous studies in which such interactions were evaluated. Based on the interactions found in the actual experimental structures we developed the first rule-based approach for predicting the ability of TCR residues in the complementarity-determining region (CDR) 1, CDR2, and CDR3 loops to interact with the MHC-peptide antigen complex. Two relatively simple algorithms show good performance under cross validation.
Proceedings of The National Academy of Sciences, 2005
CD8 ؉ T cells recognize peptides of eight to nine amino acid residues long in the context of MHC class I molecules on the surface of antigen-presenting cells (APCs). This recognition event is highly sensitive, as evidenced by the fact that T cells can be activated by cognate peptide͞MHC complex (pMHC) at extremely low densities (1-50 molecules). High sensitivity is particularly valuable for detection of antigens at low density, such as those derived from tumor cells and intracellular pathogens, which can down-modulate cognate pMHCs from the surface of APCs to evade recognition by the adaptive immune system.