Thermodynamics of T-cell receptor-peptide/MHC interactions: progress and opportunities

Abstract

alphabeta T-cell receptors (TCRs) recognize peptide antigens presented by class I or class II major histocompatibility complex molecules (pMHC). Here we review the use of thermodynamic measurements in the study of TCR-pMHC interactions, with attention to the diversity in binding thermodynamics and how this is related to the variation in TCR-pMHC interfaces. We show that there is no enthalpic or entropic signature for TCR binding; rather, enthalpy and entropy changes vary in a compensatory manner that reflects a narrow free energy window for the interactions that have been characterized. Binding enthalpy and entropy changes do not correlate with structural features such as buried surface area or the number of hydrogen bonds within TCR-pMHC interfaces, possibly reflecting the myriad of contributors to binding thermodynamics, but likely also reflecting a reliance on van't Hoff over calorimetric measurements and the unaccounted influence of equilibria linked to binding. TCR-pMHC binding heat capacity changes likewise vary considerably. In some cases, the heat capacity changes are consistent with conformational differences between bound and free receptors, but there is little data indicating these conformational differences represent the need to organize disordered CDR loops. In this regard, we discuss how thermodynamics may provide additional insight into conformational changes occurring upon TCR binding. Finally, we highlight opportunities for the further use of thermodynamic measurements in the study of TCR-pMHC interactions, not only for understanding TCR binding in general, but also for understanding specifics of individual interactions and the engineering of TCRs with desired molecular recognition properties.

Figure 1

Ribbon diagram of a complex between an αβ T cell receptor and a peptide/MHC complex. The α chain of the TCR is red and the β chain is blue. The peptide in the peptide/MHC complex is in yellow stick format, the heavy chain cyan, and β₂m is light brown. The dual recognition of peptide (non-self) and MHC (self) is evident from the figure. The figure is of the B7 TCR recognizing the Tax peptide presented by HLA-A2, PDB file 1BD2 [Ding et al., 1998].

Figure 2

Diversity in TCR-pMHC binding enthalpy and entropy changes revealed by plotting ΔH° and ΔG° vs. ΔS° at 25 °C. A) Only data for interactions involving wild-type TCRs, wild-type MHCs, and native peptides. B) All data including mutant proteins and modified peptides. For both A and B, data involving recognition of class I pMHC are shown as red triangles, data involving recognition of class II MHC are shown as blue squares, and ΔG° values for recognition of both class I and class II pMHC are shown as black circles. Errors were included when available. The lines represent linear fits to the ΔH° vs. ΔS° data. The clear linearity reflects the presence of enthalpy/entropy compensation within the data, but this only arises because ΔG° is relatively invariant with respect to ΔH° as described in the text. For panel A, the slope and intercept are 291 K and −7.3 kcal/mol and R² = 0.99. For panel B, the slope and intercept are 295 K and −7.1 kcal/mol and R² = 0.99. All data are tabulated in Table 1, and unless otherwise indicated reported at a reference temperature of 298 K (25 °C).