TCR Recognition of Peptide-MHC-I: Rule Makers and Breakers

Abstract

T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR-pMHC-I structures to date were determined within this time. Here, we review the new insights learned from these recent TCR-pMHC-I structures and their impact on T cell activation.

Keywords: MHC class I; TCR binding; human leukocyte antigen (HLA); peptide antigens; αβ TCR; γδ TCR; δβ TCR.

Figure 1

pMHC-I structure and current T cell receptor (TCR)-pMHC-I structures available. (A,B) Cleft of major histocompatibility complex (MHC)-I molecule (pale pink) represented as surface from a top-down view (A) and side view (B); the peptide is represented as pink spheres with the anchors residues at position 2 (P2) and at the last position (PΩ) in the B and F pockets (B). (C,D) Number of TCR–pMHC-I structures solved per year (C) or per MHC-I (D).

Figure 2

TCR docking on pMHC-I complex. (A) Schematic of canonical TCR docking on pMHC-I, whereby the TCRα (green) is above the MHC-I α2-helix (grey tube) and the TCRβ chain (purple) is above the MHC-I α1-helix (grey tube). (B) Schematic of reversed docking for TCR, with the arrow indicating a 180° shift from the canonical docking mode (shown on (A)). Here, the TCRα (green) is above the α1-helix, while the TCRβ chain (purple) is above the α2-helix. The peptide is represented as dots on panels (A,B). (C) Overlay of all TCR–pMHC-I structures from Table 1, aligned on the MHC-I antigen binding cleft (residues 1–180).

Figure 3

Unconventional TCR docking or TCR–peptide interactions. (A) NP2-B17 TCR (α in green and β in purple) contacting the loops outside the H-2D^b antigen-binding cleft, and, namely, the residues 18 and 89 (white stick). The red and blue dashed lines represent the hydrogen and Van der Waals interactions. (B) The NP2-B17 TCR CDR2β (cyan) and framework β (purple) interact with the NP₃₆₆ peptide (pink) presented by H-2D^b (white). (C) TRBV13-3+ TCR (β chain in blue) with the CDR1β (green) residues (sticks) interacting specifically with the malaria-derived SQL peptide (orange) P7-Lys and P8-Tyr (sticks) presented by the H-2D^b (yellow). (D) Comparison of the MMW peptide structure (loop) presented by human leukocyte antigen (HLA)-A*02:01 without (cyan) or with the DMF5 TCR (purple). The DMF5 TCR binding leads to a register shift of the MMW peptide, whereby the P10-Met^free in the HLA cleft (cyan sticks) is flipped out of the cleft (P10-Met^bound in purple stick) upon binding of the DMF5 TCR.

Figure 4

Different solutions to engage with the same pMHC-I complex. Structures of HLA-A*02:01 (white) presenting the M1 peptide in complex with the JM22 TCR (A), LS01 TCR (B), LS10 TCR (C), or F50 TCR (D). The structures were superimposed by aligning the cleft (residues 1–180) and presented in the same orientation. The M1 peptide is coloured as per the bound TCR in pink with JM22 (A), cyan with LS01 (B), orange with LS10 (C), and yellow with F50 (D), and the P5-Phe and P7-Phe are represented as sticks. The CDR3β loop is coloured in green for all TCRs, and the CDR3α is removed from all panels but (C), where its coloured in red. The sphere on panel (C) represents the Cα atom of the F50 TCR Gly99α.

Figure 5

TCR cross-reactivity and non-αβ TCR recognition. (A) Structural overlay of the 1E6 TCR in complex with the PPI (white) and altered PPI peptides: YQF (green), RQW (orange), MVW (cyan), RQF-I (pink), and RQF-A (yellow). The conserved ⁴GPD⁶ motif in the peptide is represented as sticks and spheres for the Cα atom of the P4-Gly. The CDR3 loop residue Tyr97α and Trp97β forming the hydrophobic cap are represented as sticks. (B) Structural overlay of the MAG-IC3 TCR in complex with the HLA-A*01:01 (white) presenting the MAGE-A3 (pink) or titin (cyan) peptide. The TCR is coloured as per the bound peptide, with the CDR1α in green, CDR3α in purple, and CDR3β in yellow. (C) Top view of structural overlay of δβ TCRs in complex with pHLA-I complex. The TU55 TCR-HLA-B*35:01-IPL is in green, S19-2 TCR-HLA-A24:02-RYP is in cyan, and clone 12 TCR-HLA-B*35:01-IPS is in orange. The conserved TRDV1*01 CDR1δ is represented as a loop with the Trp29δ and Trp30δ represented as sticks. (D) As per panel (C), the top view of the MHC-I cleft with a structural overlay of three δβ TCRs–pMHC-I complex and the 5F3 γδ TCR added (yellow). The mass centres for the Vβ or Vγ are represented as black spheres, while the Vδ mass centres are presented as coloured spheres matching each TCR as per panels (C,D). All the structural overlays are aligned on the MHC-I cleft (residues 1–180).

Figure 6

TCR–pMHC-I structural and biophysical parameter correlation. (A–D) Correlation between buried surface area (BSA); contribution from the Vα, Vβ, or peptide; as well as affinity (Kd) were assessed using simple linear regression calculated with Prism 8 (p ≤ 0.05 is considered as significant, ns: p > 0.05 ***: p ≤ 0.001). Derived function is coloured red if the correlation is significant and blue if not significant. The TCR–pMHC-I complexes without reported affinity (NA in Table 1) were removed as well as the engineered high affinity MAG-IC3 TCR to keep only naturally occurring TCR.