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The underlying basis of major histocompatibility complex (MHC) restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC restriction, we have examined the thermodynamic basis of a highly characterized immun...
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... temperature was plotted against the G values calculated from the affinity (Fig. 1B). Nonlinear regression was used to fit the three-parameter equation to the curve and thus calculate the thermodynamic parameters H, S, and C p (Fig. 1B and Table 1). The interaction shows an enthalpic contribution of 2.4 2.8 kcalmol and entropic contribution (TS) of 4.2 2.6 kcalmol with a C p of 0.62 0.27 kcalmol at 25°C. ...
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... the integrated peak area vs. TcR concentration revealed that the interaction has an affinity of 8.1 2.7 M, an enthalpy of 3.6 0.5 kcalmol, and a favorable entropic contribution of 11.5 2.2 calmol (TS 3.4 0.7 kcalmol at 25°C). Thus, the param- eters derived from fitting the three-parameter equation to the SPR data were in close agreement with the ITC measurements (Table 1) as noted previously in thermodynamic studies of TcR-pMHC-I interactions (13,14). Heat Capacity of the Interaction of LC13 and FLR-HLA-B8 Is Normal. ...
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... C p (C p,conf ), that is, the heat capacity change that cannot be attributed to the static structures and is believed to be a result of conformational change andor change in flexibility, is determined by C p,obs C p,calc (13). Computational assessment of the change in the polar and nonpolar accessible surface area on binding of LC13 TcR to FLR-HLA-B8 by using the crystal structures of the liganded and unliganded LC13 TcR (10, 17) yielded a C p,calc of 0.25 kcal molK and a C p,conf of 0.37 kcalmolK (Table 1). This C p,calc is consistent with that of other TcR-pMHC-I interactions. ...
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... On the other hand, a ranking of the four peptides is not possible as the differences are small and within the statistical uncertainty. While the structural rigidity of the pMHC would result in a higher entropic cost of association to the TCR, several studies of TCR/pMHC complexes have reported on the importance of enthalpic contributions (35)(36)(37). The thermodynamic stability of the complex is the result of both entropic and enthalpic factors. ...
T-cell receptor (TCR) recognition of myelin basic protein (MBP) peptide presented by major histocompatibility complex (MHC) protein HLA-DR2a, one of the MHC class II alleles associated with multiple sclerosis, is highly variable. Interactions in the trimolecular complex between the TCR of MBP83-99-specific T cell clone 3A6 with the MBP-peptide/HLA-DR2a (abbreviated TCR/pMHC) lead to substantially different proliferative responses when comparing the wild-type decapeptide MBP90-99 and a superagonist peptide which differs mainly in the residues that point towards the TCR. Here we investigate the influence of the peptide sequence on the interface and intrinsic plasticity of the TCR/pMHC trimolecular and pMHC bimolecular complexes by molecular dynamics simulations. The intermolecular contacts at the TCR/pMHC interface are similar for the complexes with the superagonist and the MBP self-peptide. The orientation angle between TCR and pMHC fluctuates less in the complex with the superagonist peptide. Thus, the higher structural stability of the TCR/pMHC tripartite complex with the superagonist peptide, rather than a major difference in binding mode with respect to the self-peptide, seems to be responsible for the stronger proliferative response.
... 22 However, although the general TCR-pMHC binding mode is similar, the flexibility and structural and energetic versatility of this interaction (Fig. 3) has made it difficult, if not controversial, to identify a fixed set of structural rules that explain the general binding mode. 4,[61][62][63][64][65][66] For example, during antigen binding, TCRs can "tilt" over a 45 range (relative to the pMHC cleft) [ Fig. 3(A)], they can bind centrally, or towards the N-and C-terminus of the peptide [ Fig. 3(B)], and they can "swivel" over the pMHC surface at a wide range of angles (32 -80 ) [Fig. 3(C)]. ...
The T-cell antigen receptor is a heterodimeric α protein (TCR) expressed on the surface of T-lymphocytes, with each chain of the TCR comprising three complementarity-determining regions (CDRs) that collectively form the antigen-binding site. Unlike antibodies, which are closely related proteins that recognize intact protein antigens, TCRs classically bind, via their CDR loops, to peptides (p) that are presented by molecules of the Major Histocompatibility Complex (MHC). This TCR-pMHC interaction is crucially important in cell-mediated immunity, with the specificity in the cellular immune response being attributable to MHC polymorphism, an extensive TCR repertoire and a variable peptide cargo. The ensuing structural and biophysical studies within the TCR-pMHC axis have been highly informative in understanding the fundamental events that underpin protective immunity and dysfunctional T-cell responses that occur during autoimmunity. In addition, TCRs can recognize the CD1 family, a family of MHC-related molecules that instead of presenting peptides are ideally suited to bind lipid-based antigens. Structural studies within the CD1-lipid antigen system are beginning to inform us how lipid antigens are specifically presented by CD1, and how such CD1-lipid antigen complexes are recognized by the TCR. Moreover, it has recently been shown that certain TCRs can bind to vitamin B based metabolites that are bound to an MHC-like molecule termed MR1. Thus, TCRs can recognize peptides, lipids and small molecule metabolites, and here we review the basic principles underpinning this versatile and fascinating receptor recognition system that is vital to a host's survival.
... (i) The temperature (Boulter et al., 2007;Ely et al., 2006;Gakamsky et al., 2007;Miles et al., 2010), the pH ( et al., 2001) and the amount of ligand immobilized onto the sensorchip (Dimmock & Hardy, 2004;Zhang & Oglesbee, 2003). (ii) The alternative use of the two binders as immobilized ligand or as free analyte, that can generate contrasting results: a few papers reported similar binding parameters independent of the binder chosen for immobilization (Chaloin et al., 2005), while usually binding parameters are reported that can be of magnitude of one order different depending on the alternative immobilization of one of the two binders (Bernet et al., 2004;Waddington et al., 2008;Zhao et al., 2005). ...
Abstract Despite decades of antiviral drug research and development, viruses still remain a top global healthcare problem. Compared to eukaryotic cells, viruses are composed by a limited numbers of proteins that, nevertheless, set up multiple interactions with cellular components, allowing the virus to take control of the infected cell. Each virus/host interaction can be considered as a therapeutical target for new antiviral drugs but, unfortunately, the systematic study of a so huge number of interactions is time-consuming and expensive, calling for models overcoming these drawbacks. Surface plasmon resonance (SPR) is a label-free optical technique to study biomolecular interactions in real time by detecting reflected light from a prism-gold film interface. Launched 20 years ago, SPR has become a nearly irreplaceable technology for the study of biomolecular interactions. Accordingly, SPR is increasingly used in the field of virology, spanning from the study of biological interactions to the identification of putative antiviral drugs. From the literature available, SPR emerges as an ideal link between conventional biological experimentation and system biology studies functional to the identification of highly connected viral or host proteins that act as nodal points in virus life cycle and thus considerable as therapeutical targets for the development of innovative antiviral strategies.
... However, SPR has proven in most cases to be an excellent technique when comparing TCR affinities for different ligands, with a good correlation to functional studies [22][23][24][25]. While early thermodynamic experiments with SPR suggested that TCR/pMHC interactions were governed by enthalpically favorable and entropically unfavorable thermodynamics [4,[26][27][28][29][30][31][32], more recent studies clearly demonstrated that recognition of pMHCs by TCRs could also be entropically driven [4,5,13,15,30,33]. Thus at the present time, no clear-cut conclusions can be drawn regarding the strategy used by TCRs in order to recognize their cognate ligands. ...
... Favorable entropy changes commonly arise from desolvation, whereby ordered waters are expulsed from apolar surfaces upon binding, leading to an increase in total entropy of the system [35]. The release of water molecules upon binding of a TCR to a pMHC can thus result in a favorable entropy pathway for recognition, as clearly demonstrated in a previous study [29]. In contrast, poor shape complementary between TCRs and pMHC interfaces may result in formation of cavities that can trap waters, as observed in several TCR/pMHC crystal structures [29,34]. ...
... The release of water molecules upon binding of a TCR to a pMHC can thus result in a favorable entropy pathway for recognition, as clearly demonstrated in a previous study [29]. In contrast, poor shape complementary between TCRs and pMHC interfaces may result in formation of cavities that can trap waters, as observed in several TCR/pMHC crystal structures [29,34]. Trapped water molecules can form hydrogen bonds, thus contributing positively to the binding enthalpy in TCR interactions. ...
The molecular basis underlying T-cell recognition of MHC molecules presenting altered peptide ligands is still not well-established. A hierarchy of T-cell activation by MHC class I-restricted altered peptide ligands has been defined using the T-cell receptor P14 specific for H-2D(b) in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM). While substitution of tyrosine to phenylalanine (Y4F) or serine (Y4S) abolished recognition by P14, the TCR unexpectedly recognized H-2D(b) in complex with the alanine-substituted semiagonist Y4A, which displayed the most significant structural modification. The observed functional hierarchy gp33 > Y4A > Y4S = Y4F was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H-2D(b) /gp33 was strictly enthalpy driven, recognition of the weak agonist H-2D(b) /Y4A was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P14 with H-2D(b) /gp33 compared with H-2D(b) /Y4A can possibly be explained by higher water entrapment at the TCR/MHC interface, which is also consistent with the measured opposite entropy contributions for the interactions of P14 with both MHCs. In conclusion, this study demonstrates that P14 makes use of different strategies to adapt to structural modifications in the MHC/peptide complex.
... Whether this hidden logic is underpinned by germline-encoded TCR-MHC recognition remains an area of intense investigation (7)(8)(9)(10)(11). The insight gleaned from TCR-pMHC-I structural studies have been bolstered significantly by associated biophysical, thermodynamic, and mutational studies, which have shown that the relative energetic contributions from the CDR loops can vary between different TCR-pMHC systems (7,(12)(13)(14)(15)(16)(17)(18)(19). To date, most of the structural/mutagenesis studies have focused on TCR recognition of short peptides (8 -10 amino acids), whereas it is known that ϳ5-10% of the repertoire of peptides bound to MHC-I can be longer than 10 amino acids in length (20,21). ...
Although the major histocompatibility complex class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, "bulged" peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13-amino acid viral peptide (LPEPLPQGQLTAY) complexed to human leukocyte antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508(LPEP) complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). Although the structural footprint on HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region 3α and germline-encoded complementarity determining region 1β loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation toward a bulged pMHC-I complex.
... 31,32 Thermodynamic experiments have extended our understanding of this phenomenon, showing that TCR/pMHC binding is typically characterized by a negative TDS o , or a loss of entropy, which suggests that there is a transition from disorder to order during binding. [33][34][35][36] Although we do not fully understand the molecular rules that govern T-cell specificity, it is clear that the TCR is exquisitely tuned so that it can recognize foreign epitopes with sufficient strength to initiate activation, while remaining largely tolerant and inactive to self tissue. Accumulated biophysical data have complemented structural studies and shed light on the parameters that underpin this fine dichotomy. ...
The molecular rules that govern MHC restriction, and allow T-cells to differentiate between peptides derived from healthy cells and those from diseased cells, remain poorly understood. Here we provide an overview of the structural constraints that enable the T-cell receptor (TCR) to discriminate between self and non-self peptides, and summarize studies that have attempted to correlate the biophysical parameters of TCR/peptide–major histocompatibility complex (pMHC) binding with T-cell activation. We further review how the antigenic origin of peptide epitopes affects TCR binding parameters and the ‘quality’ of a T-cell response. Understanding the principles that govern pMHC recognition by T-cells will unlock pathways to the rational development of immunotherapeutic approaches for the treatment of infectious disease, cancer and autoimmunity.
... However, there have been notable examples wherein the CDR1 and/or CDR2 loops directly contact the peptide 5,20 or wherein the CDR3 loop is energetically important for contacting the MHC. 21,22 In a comparison of pMHC recognition by TCRs bearing the Vb8.2 variable segment, closely related TCRs were found to show similar docking modes on the pMHC. 16,17 However, Vb8.2 TCRs that recognize the MHC-like molecule, CD1d, exhibit a markedly different docking mode. ...
αβ T-cell receptors (TCRs), which can engage a broad array of foreign peptide-laden major histocompatibility complex (pMHC) landscapes, have an essential role in protective immunity. TCRs are selected by pMHC molecules in the thymus and in the periphery, and so are restricted to recognizing 'self'-major histocompatibility complex (MHC) molecules. Accordingly, T cells are inherently cross-reactive, and although the versatility and specificity of this MHC-restricted response are the hallmarks of adaptive immunity, 'unwanted' TCR interactions, such as those observed in T-cell alloreactivity, often occur. Recent data have shown that direct T-cell alloreactivity can arise from peptide-dependent molecular mimicry, as well as distinct pMHC-binding modes. Here we review recent advances in the field, focusing on structural data pertaining to alloreactivity, and discuss the implications for T-cell-mediated transplant rejection.
... This was especially of interest given that structures of the A6 TCR bound to multiple different peptide/MHC molecules showed that the TCR is capable of conformational shifts to accommodate various binding partners (32,45). In 2006, the entropically driven LC13-FLR/HLA-B8 interaction was characterized by Ely et al. (69). ...
... Rather, van't Hoff analysis is performed on surface plasmon resonance data and relies on accurate and precise free energy measurements across a wide temperature range (111,139). Indeed, reports showing good agreement between thermodynamic data measured via SPR and calorimetry require a high quality of SPR data, which is not necessarily achievable in moderate affinity systems (69,162,171). ...
... The earlier thermodynamic data were not determined calorimetrically, but by fitting binding free energies measured by surface plasmon resonance as a function of temperature. Although a number of reports show good agreement between SPR and calorimetrically measured thermodynamic data(69,161,162), achieving close agreement places considerable demands on the accuracy and precision of the individual free energy measurements, which can be difficult to achieve when weak-to-moderate affinity interactions are studied with SPR.Another difference between the two experiments is the buffer and pH used:HEPES, pH 7.4 was used in the SPR experiment, whereas imidazole, pH 6.4 was used in the ITC experiment. Aside from the influence of direct buffer-protein interactions(149), buffer and pH choice can have a dramatic influence on ligand binding thermodynamics when binding is linked to changes in protonation states (i.e., a pK a shift occurs upon binding) (82, 102). ...
... This method examines the dependence of the binding affinity on temperature to extract thermodynamic information about a protein-protein interaction. The use of van't Hoff analysis to study the thermodynamics of TCR-pMHC interactions has been reported in the past (Boniface et al., 1999;Garcia et al., 2001;Lee et al., 2004) and shown in several studies to give similar results to microcalorimetry (Davis-Harrison et al., 2005;Ely et al., 2006;Krogsgaard et al., 2003;Willcox et al., 1999). ...
... kcal/mol) ( Figure 2C; Table 1). Similar to most other TCR-pMHC interactions that have been examined, each of the TCR-pMHC pairs examined showed a negative ΔC P (ranging from -0.29 to -1.12 kcal/mol-K), consistent with the burial of hydrophobic surface area upon binding (Ely et al., 2006;Krogsgaard et al., 2003). ...
... In both cases, binding to M15 was more favorable enthalpically with a compensating entropy penalty, compared to Hb/I-E k . One might anticipate such dramatic enthalpy-entropy compensation with recognition of structurally very different pMHC ligands (Mazza et al., 2007), or with structurally very different TCRs (Anikeeva et al., 2003;Davis-Harrison et al., 2005;Ely et al., 2006). ...
Interactions between the T cell receptor and cognate peptide-MHC are crucial initiating events in the adaptive immune response. These binding events are highly specific yet occur with micromolar affinity. Even weaker interactions between TCR and self-pMHC complexes play critical regulatory roles in T cell development, maintenance and coagonist activity. Due to their low-affinity, the kinetics and thermodynamics of such weak interactions are difficult to study. In this work, we used M15, a high-affinity TCR engineered from the 3.L2 TCR system, to study the binding properties, thermodynamics, and specificity of two altered peptide ligands (APLs). Our affinity measurements of the high-affinity TCR support the view that the wild type TCR binds these APLs in the millimolar affinity range, and hence very low affinities can still elicit biological functions. Finally, single methylene differences among the APLs gave rise to strikingly different binding thermodynamics. These minor changes in the pMHC antigen were associated with significant and unpredictable changes in both the entropy and enthalpy of the reaction. As the identical TCR was analyzed with several structurally similar ligands, the distinct thermodynamic binding profiles provide a mechanistic perspective on how exquisite antigen specificity is achieved by the T cell receptor.
... This effect can be seen for the influenza A virus D b NP 366 -secific response, where there is initial recruitment of a broad spectrum of (presumably) low avidity CD8 + T cells that (while they may persist into memory) remain CD62L hi and never expand [33]. Where such narrowing is not observed, compensatory mechanisms related to CD4 and CD8 coreceptor binding may serve to stabilize some less optimal TCR-pMHC interactions [34] and effectively reduce the activation threshold [35]. The interplay between co-receptor and TCR-pMHC avidity may thus serve to promote greater TCR diversity in antigen-selected TCR repertoires [36]. ...
Naive T cells are recruited into any given host response by recognizing a spectrum of possible antigens with 'sufficient' avidity. Does selecting a more functionally diverse array give better immune control? Perhaps low avidity 'killers' that 'kiss and run' operate optimally to eliminate virus-infected targets, while high avidity 'helpers' that stay faithfully in place produce more cytokine. Recent findings indeed suggest that the selection of a broad T cell receptor repertoire is characteristic of the initial phase following antigen contact, while continued exposure leads to further cycles of division and the progressive numerical dominance of 'best-fit' clonotypes. Here, we review recent advances demonstrating a link between T cell repertoire diversity and immunity to infection, and consider the potential mechanisms at play.
