The versatility of the αβ T-cell antigen receptor

Abstract

The T-cell antigen receptor is a heterodimeric αβ 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.

Keywords: T-cell receptor; antigen presenting molecules; immune system; structures.

Figure 1

Peptide and nonpeptide antigens. (Top) Consensus peptide motifs for some HLA (Human Leukocyte Antigens; human homologues of murine MHC class I and class II proteins) molecules are shown as determined by the SYFPEITHI database. Amino acids occupying peptide binding sites “p,” on HLA molecules are denoted by their single letter amino acid code. “—,” negatively charged sidechain; “b,” bulky sidechain; “#,” hydrophobic; “δ,” charged; Amino acids that serve as anchoring residues are depicted in bold, auxiliary anchoring residues are denoted by an adjacent “*.” Preferred amino acids at peptide binding sites that are not anchors are denoted in normal type font. (Middle) Nonpeptide antigens presented by CD1 proteins. (Bottom) Vitamin B metabolites presented on MR1.

Figure 2

A structural comparison of pMHC-I and pMHC-II. Although the subunit compositions of (A) MHC-I (PDB: 2AK4) and (B) MHC-II (PDB: 3S4S) are different, the structural conformation they assume is very similar, illustrating their shared role in presenting antigenic peptides (red) to T-cells. (A) MHCI is comprised of 3 α-chain domains (α1, α2, and α3 in blue) and β2m (cyan), whereas (B) MHCII is comprised of a 2 domain α-chain (blue) and a 2 domain β-chain (cyan). (C) A top down view of the MHCI binding cleft demonstrating the closed conformation of the cleft and (D) the MHCII binding cleft demonstrating how the open cleft enables the peptide to extend from either end (colors as in A and B). (E) Side view of pMHCI showing how the closed conformation of the cleft forces the central residues of the peptide up in a bulged conformation. (F) Side view of pMHCII showing how the open ended peptide binding cleft enables the peptide to lie flat and extend out of either end generating peptide flanking regions.

Figure 3

Comparison of different TCRs binding to pMHC. (A) Alignment (using MHC as the aligning molecule) of a range of previously published TCR-pMHC-I structures (PDB: 3GSN, 3H9S, 3KPS, 3MV7, 1BD2, 1MI5, 1AO7, 2BNR, 1OGA, 2NX5, 2AK4, 3DXA, 3O4L, 1LP9, 3FFC, 3HG1, and 3UTS60) (TCRs in multicolored cartoon, pMHC-I in gray cartoon and surface) showing the range of TCR “tilt” relative to the pMHC during binding. (B) Although the TCRα-and β-chains remain in a generally fixed orientation over the pMHC surface (gray cartoon and surface), the positions of the TCR CDR loops (multicolored cartoon) are extremely variable between different TCR-pMHC-I complexes and can bind centrally, or towards the N-or C-terminus of the peptide. (C) Representation of the “swivel” range of docking angles used by TCRs when contacting pMHC surfaces.

Figure 4

Docking modes of TCR-pMHC, NKT TCR-CD1d-lipid, and MAIT TCR-MR1-metabolite complexes. (A) TCR-pMHC1 complex, pdb code; 1MI5. (B) A TCR-pMHCII ternary complex, pdb code;1FYT. (C) A human NKT TCR in complex with CD1d-α-galactosylceramide (αGalCer), pdb code; 2PO6. (D) MAIT TCR in complex with MR1-ribityl derivative, pdb code; 4LCW. The antigen binding face of each antigen presenting molecule (ribbon, middle panel; surface, bottom panel) with respective ligands depicted in stick (A–C) or spheres (D).