MHC binding affects the dynamics of different T-cell receptors in different ways

Abstract

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.

Fig 1. TCRpMHC structure.

(A) The TCR (white) on top of the peptide (blue) and MHC (transparent grey) is shown. CDR1α (red, left), CDR2α (orange, left), CDR3α (green, left), CDR1β (red, right), CDR2β (orange, right), and CDR3β (green, right) of the TCR are in contact with the peptide/MHC complex. (B) Same as (A) but as top-view from the perspective of the TCR (only the CDRs of the TCR are shown) on the peptide/MHC (only the α₁ and α₂ regions of the MHC are shown). (C) Superimpositions of all four TCRs of this study. The LC13 (white), JM22 (violet), A6 (cyan) and 1G4 (light blue) TCR share a similar overall structure. (D) Same as (C) but superimposition of the MHCs (bottom). Despite their similar structure the four TCRs have slightly different binding modes on the MHCs.

Fig 2. Distances between CDR3α and CDRβ as histograms.

The x-axis shows the distance while the y-axis shows the occurrence of this value over all replicas and all time steps. (A) Distance of the LC13 TCR. (B) Distance of the JM22 TCR. (C) Distance of the A6 TCR. (D) Distance of the 1G4 TCR.

Fig 3. Radius of gyration of the CDR3α regions of the four TCRs.

The x-axis shows the radius of gyration while the y-axis shows the occurrence of this value over all replicas and all time steps. (A) RG of the LC13 TCR. (B) RG of the JM22 TCR. (C) RG of the A6 TCR. (D) RG of the 1G4 TCR.

Fig 4. Solvent accessible surface area of CDR3α for the LC13, JM22, A6 and 1G4 TCR.

The SASA measurements were taken one time with all involved structures (i.e. based on TCRpMHC for TCRpMHC and based on TCR for TCR) and a second time based only on the TCR (i.e. based on TCR for TCRpMHC and based on TCR for TCR). The x-axis shows the SASA while the y-axis shows the occurrence of this value over all replicas and all time steps. (A) SASA of CDR3α of the LC13 TCR. (B) SASA of CDR3α of the JM22 TCR. (C) SASA of CDR3α of the LC13 TCR measured without MHC. (D) SASA of CDR3α of the JM22 TCR measured without MHC. (E) SASA of CDR3α of the A6 TCR. (F) SASA of CDR3α of the 1G4 TCR. (G) SASA of CDR3α of the A6 TCR measured without MHC. (H) SASA of CDR3α of the 1G4 TCR measured without MHC.

Fig 5. RMSF of the TCR on a per residue basis.

Thick lines indicate mean values of TCRpMHC and TCR simulations while dashed lines indicate the standard error of mean. Horizontal lines mark specific regions of interest. The vertical lines at 200 indicate the border between TCR α- and β-chain. Permutation test for these regions can be found in Table 2. (A) RMSF of the LC13 TCR. (B) RMSF of the JM22 TCR. (C) RMSF of the A6 TCR. (D) RMSF of the 1G4 TCR. Please note that the RMSF curve of (A) is smoother than the others due to the use of 100 replicas instead of 10.

Fig 6. Number of H-bonds between the TCR α and β chain.

The x-axis shows the number of H-bonds while the y-axis shows the occurrence of this number over all replicas and all time steps. (A) LC13 TCR. (B) JM22 TCR. (C) A6 TCR. (D) 1G4 TCR.

Fig 7. 3D visualisation of H-bond patterns within the four TCRs based on PyHVis3D [14].

The radius of the cylinders is proportional to the difference between TCRpMHC simulations and TCR simulations where red cylinders indicate more H-bonds in TCRpMHC simulations while blue cylinders indicate more H-bonds in TCR simulations. Only H-bonds with a difference > 6% are shown as a boot strapping analysis (S1 Fig) indicates that theseH-bonds would not be seen by chance. TCR α-chain (white), TCR β-chain (dark grey), and peptide/MHC head (transparent white) are shown aligned by TCR orientation.