Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jul;181(1):1-18.
doi: 10.1111/cei.12622. Epub 2015 May 14.

The T Cell Antigen Receptor: The Swiss Army Knife of the Immune System

Affiliations
Free PMC article
Review

The T Cell Antigen Receptor: The Swiss Army Knife of the Immune System

M Attaf et al. Clin Exp Immunol. .
Free PMC article

Abstract

The mammalian T cell receptor (TCR) orchestrates immunity by responding to many billions of different ligands that it has never encountered before and cannot adapt to at the protein sequence level. This remarkable receptor exists in two main heterodimeric isoforms: αβ TCR and γδ TCR. The αβ TCR is expressed on the majority of peripheral T cells. Most αβ T cells recognize peptides, derived from degraded proteins, presented at the cell surface in molecular cradles called major histocompatibility complex (MHC) molecules. Recent reports have described other αβ T cell subsets. These 'unconventional' T cells bear TCRs that are capable of recognizing lipid ligands presented in the context of the MHC-like CD1 protein family or bacterial metabolites bound to the MHC-related protein 1 (MR1). γδ T cells constitute a minority of the T cell pool in human blood, but can represent up to half of total T cells in tissues such as the gut and skin. The identity of the preferred ligands for γδ T cells remains obscure, but it is now known that this receptor can also functionally engage CD1-lipid, or immunoglobulin (Ig) superfamily proteins called butyrophilins in the presence of pyrophosphate intermediates of bacterial lipid biosynthesis. Interactions between TCRs and these ligands allow the host to discriminate between self and non-self and co-ordinate an attack on the latter. Here, we describe how cells of the T lymphocyte lineage and their antigen receptors are generated and discuss the various modes of antigen recognition by these extraordinarily versatile receptors.

Keywords: CD1; MHC-I; MHC-II; MHC-Ib; MR1; T cell; T cell receptor; αβ TCR; γδ TCR.

Figures

Figure 1
Figure 1
Generation of αβ and γδ T cell receptors (TCRs) by V–(D)–J recombination. (a) The tra/trd locus consists of a cluster of 46 functional T cell receptor alpha variable (TRAV) segments and eight T cell receptor delta variable (TRDV) segments, followed by three segments in the T cell receptor delta diversity (TRDD) cluster and four segments in the T cell receptor delta joining (TRDJ) cluster. A total of 51 functional TRAV segments lie between the TRDC and the T cell receptor alpha chain constant region (TRAC) segments. At the tra/trd locus, V–J recombination brings together one of many TRAV segments and one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) The trb locus comprises 48 functional T cell receptor beta variable (TRBV) segments followed by two D segments, 12 functional TRBJ segments and two TRBC segments. For TCR-β chain rearrangements, V–(D)–J recombination is a two-step, ordered process. D–J recombination occurs first, juxtaposing TRBD1 to one of many TRBJ1 segments or TRBD2 to one of many TRBJ2 segments. V–DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which V, D, J and C segments are directly adjacent. (c) The trg locus is composed of six functional TRGV segments and five TRGJ segments followed by two TRGC segments. At the trg locus, V–J recombination joins one of many TRGV segments to a TRGJ segment. Similar to TCR-α chains, the intervening regions are spliced, producing a TCR-γ transcript in which V, J and C segments are directly adjacent. (d) The generation of TCR-δ chains also occurs at the tra/trd locus. The 5′ end of this locus consists of a cluster of V genes. All V genes in this cluster can recombine with TRAJ, but only a subset can recombine with TRDD. Thus, many V genes in the tra/trd locus are used exclusively for TCR-δ rearrangement in early thymic precursors, while others are used exclusively for TCR-α rearrangement in double-positive thymocytes. Some V genes can be used interchangeably. Similar to TCR-β chains, TCR-δ chains are produced by V–(D)–J recombination and splicing, producing a final transcript in which V, D, J and C segments are directly juxtaposed. Unlike the TCR-β chain, however, TCR-δ can incorporate multiple D segments.
Figure 2
Figure 2
Structure of T cell receptor (TCR) proteins and mRNA. (a) αβ [Protein Data Bank (PDB): 3HG1] and γδ (PDB: 1HXM) . TCRs adopt similar tertiary structures that position the complementarity-determining regions (CDR) loops at the membrane distal end of the molecules. Together the six CDR loops form the antigen binding site. (b) The mRNA structures show that for each chain CDR1 and CDR2 are encoded in the germline. CDR3 is the product of junctional diversity at V–J joins of T cell receptor (TCR)-α and TCR-γ chains and V–D–J joins in TCR-β and TCR-δ chains. CDR3 is consequently hypervariable. The colour code adopted for the CDR loops is maintained throughout this paper. The areas coloured in grey represent the constant and variable domains of the TCRs (not including the hypervariable CDR loops).
Figure 3
Figure 3
The structures of peptide-major histocompatibility complex class I (pMHC-I) and class II (pMHC-II). The two classes of classical MHC adopt similar overall structures despite being differently comprised. MHC-I [Protein Data Bank (PDB): 1ZHL] (a) consists of a variable heavy chain (grey) folded with the invariant β-2-microglobulin molecule (cyan). (b) The ends of the MHC-I peptide-binding groove are closed. MHC-I presents peptides of 8–14 amino acids in length to T cells. (c) An 8-mer peptide can lie flat in the MHC-I groove. As additional amino acid residues are added, peptides have to bulge upwards and outwards in order to be accommodated within the groove. It has recently been established that MHC-I restricted T cells can recognize the length of a peptide in addition to its amino acid sequence (PDB: 1ZHL, 1XH3, 2FZ3, 3BW9, 1A1N, 1JF1, 1HHI) ,–, whereas MHC-II (PDB: 1KG0) (d) consists of an a-chain (grey) and a b-chain (cyan). Both MHC-I and MHC-II fold to present peptide (red) to T cells within a peptide-binding groove. (e) The open ends of the MHC-II peptide-binding groove allow presented peptides to extend at both the N- and C-terminus. Thus, MHC-II generally presents longer peptides than MHC-I. This mode of binding also means that the MHC-II can sometimes present the same peptide in different registers by using different amino acid side chains for anchoring into the MHC-binding pockets. (f) The open-ended MHC-II binding groove enables longer peptides to form an elongated conformation with peptide N- and C-terminal peptide flanking regions extending outside of the groove (PDB: 1KG0, 1UVQ, 2SEB, 2IAN) ,–.
Figure 4
Figure 4
T cell receptor (TCR)–peptide-major histocompatibility complex (pMHC) structures. MHC molecules (in grey) and peptide (in red sticks) are overlaid with the docking footprints of the individual complementarity-determining regions (CDR) loops of the cognate αβTCR. The coloured footprints correspond to the colours of the CDR loops shown in Fig. 2. (a) Structure of MHC-I molecule HLA-A*0201 presenting the immunodominant GLCTLVAML peptide from Epstein–Barr virus (EBV) [Protein Data Bank (PDB): 3O4L] . The coloured footprint shows how the CDR loops of the AS01 TCR sit on the pMHC complex. This complex adopts a canonical conformation where the germline-encoded CDR1 and 2 loops contact mainly the MHC and the hypervariable CDR3 loops sit over the peptide. (b) Structure of the MS2-3C8TCR docked on the MHC class II molecule human leucocyte antigen (HLA)-DR4. Here, HLA-DR4 presents a peptide from myelin basic protein (PDB: 3O6F) . (c) Overlay of all MHC-I (grey cartoon and surface)-restricted TCRs (multi-coloured) in which co-complex structures have been solved. All complexes were aligned on the MHC-I molecule to demonstrate the flexible nature of TCR–pMHC binding.
Figure 5
Figure 5
CD8 and CD4 co-receptors bind to invariant parts of peptide-major histocompatibility complex class I (pMHC-I) and pMHC-II, respectively. (a) Structural model of a T cell receptor (TCR)–pMHC-I–CD8 tripartite interaction [Protein Data Bank (PDB): 3O4L and 1AKJ] ,. MHC-I (grey cartoon) forms the peptide binding cleft using its α1 and α2 domains. The membrane distal face of the molecule comprises the TCR (blue and slate cartoon) docking platform. CD8 (green and yellow cartoon) binds at a distinct site on the α3 domain of the molecule. The structure shown is human leucocyte antigen (HLA) A*0201 and a CD8αα homodimer . (b) Tripartite complex structure of the TCR–pMHC-II–CD4 interaction (CD4 shown in orange cartoon) (PDB: 3T0E) . Similar to the TCR–pMHC-I–CD8 model, the CD4 co-receptor binds to an invariant site distal from the TCR binding platform.
Figure 6
Figure 6
The plasticity of αβ T cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC). Individual TCRs use multiple mechanisms to bind to pMHC. These effects can increase the number of individual peptides that can be recognized. (a) Macro-level changes enable the TCR to bind pMHC with an altered angle or altered register. The cartoon shows the ‘footprints’ of TCR complementarity-determining region (CDR) loops projected down onto the pMHC. (b) Relatively micro-level flexibility in the CDR loops allows them to accommodate a variety of different shapes. The cartoon shows a side view of a TCR engaging pMHC. (c) The existing database of TCR–pMHC structures indicates that TCRs tend to focus interaction on two to four upward-facing amino acid residues in the antigenic peptide (so-called ‘hotspots’ 63). In this example a TCR might focus on two amino acids in the peptide (shown in red). Such residue-focused interaction then allows the TCR to accommodate multiple amino acid substitutions at other positions in the peptide (indicated by the use of different colours on the right). The three mechanisms described above are not mutually exclusive and represent just some of the possibilities. Many residues can also bind in individual MHC binding pockets. It is now understood that altering a primary MHC anchor can substantially change the way that a peptide might be viewed by incoming T cells ,.
Figure 7
Figure 7
The peptide cross-reactivity of conventional T cells can be varied. In order to be positively selected in the thymus, a T cell must bear a T cell receptor (TCR) that allows it to recognize – and respond to – self-peptide. It should not respond to this peptide thereafter. T cell cross-reactivity could be regulated throughout the lifetime of a T cell. (a) Co-inhibitory (in red) or (b) co-stimulatory signals (in green) are likely to decrease and increase the number of ligands that can be recognized by tuning the sensitivity of TCR engagement that a T cell responds to. (c) The co-receptors, CD4 and CD8 (in purple), represent a special class of co-stimulation as these receptors bind to the same peptide–major histocompatibility complex (pMHC) ligand at the TCR. This could allow the co-receptors to discriminate between different TCR–pMHC dwell times and thus tune a T cell to recognize only certain ligands . Regulation of the cell surface expression and/or glycosylation of key receptors might also be used to vary sensitivity to cross-reactive TCR ligands.
Figure 8
Figure 8
T cell cross-reactivity causes autoimmunity. T cells bearing autoreactive T cell receptors (TCRs) sometimes escape from thymic culling and populate the peripheral tissues. Such cells usually bear TCRs that bind very weakly to self-peptide and generally remain harmless. However, if such a T cell becomes activated in response to a pathogen-derived peptide it will be stimulated to become an effector T cell. Antigen-experienced cells are known to be more sensitive to TCR triggering. Activation of such cells by a cross-recognized self-peptide could then result in autoimmune attack.
Figure 9
Figure 9
Soluble T cell receptor (TCR) therapy. (a) The MHC-I antigen presentation pathway is predicted to present at least one peptide from any protein present in a cell at 500 copies or more. This clever system allows the TCRs on the surface of MHC-I-restricted T cells to inspect the cellular proteome from the cell surface and detect internal anomalies. This ‘X-ray vision’ allows TCRs to access a far greater number of cellular targets than are available to monoclonal antibodies. Phage-display and directed evolution of TCRs can generate very high-affinity molecules (KD < 10 pM) that bind to the cognate peptide-MHC (pMHC) with very long half-lives (several hours). These molecules can then be used to deliver therapeutic payloads to specific cells in vivo. (b) High-affinity tumour-specific TCRs can be ‘fused’ to a CD3-specific Fab fragment to produce a bi-specific molecule. Such molecules have recently been used to induce cancer regression .
Figure 10
Figure 10
CD1a–d presentation of lipids. (a) CD1a can bind lipids not endowed with polar headgroups. Such lipids do not disrupt the T cell receptor (TCR)-activating conformation of the CD1a molecule. The presented ligand is lysophosphatidylcholine (LPC) [Protein Data Bank (PDB): 4X6E] . (b) CD1b can potentially present the largest and most diverse lipids of all CD1-family proteins. The lipid ligands can possess one, two or three alkyl chains buried in the hydrophobic pockets of CD1b while their polar headgroup can be recognized by germline-encoded mycolyl-reactive (GEM) T cells. The presented ligand is ganglioside GM2 (PDB: 1GZP) . (c) CD1c can present mycobacterial lipids such as phosphomycoketide (shown) to αβ T cells (PDB: 4ONO) . (d) CD1d can present self-derived lipids such as sulphatide (shown) or α-galactosylceramide (α-GalCer) to both αβ [type I and II natural killer (NK) T cells] and γδ T cells (PDB: 4MQ7) .
Figure 11
Figure 11
Recognition of antigen by ‘unconventional’ T cell receptors (TCRs). (a) Type I natural killer (NK) TCR recognition. The TCR binds CD1d–α-galactosylceramide (αGalCer) in a parallel docking mode. The recognition is markedly different from any known αβ TCR–peptide-MHC (pMHC) interactions [Protein Data Bank (PDB): 3VWK] . (b) Recognition of CD1a-lipid complex. αβ TCR recognizes a permissive conformation of CD1a surface that depends on the nature of the lipid ligand bound by the latter. Contrary to TCR-CD1d structures, no direct interactions between TCR and a lipid ligand bound to CD1a have been observed (PDB: 4X6C) . (c) Mucosal-associated invariant T (MAIT) TCR recognition of MR1. MR1 can present both activating (riboflavin precursors) and non-activating (folic acid precursors) intermediates from vitamin B biosynthetic pathways. The recognition of MR1 is mediated by conserved, invariant residues in an innate-like manner. The activating metabolites directly contact the TCR while no such interactions are observed for the non-activating metabolites (PDB: 4L4V) . (d) A hybrid δ/αβ TCR binds the CD1d-αGalCer complex. The TCR is composed of a variable Vδ1 domain fused with joining and constant α domains, and paired to a TCR-β chain. TCR-CD1d interactions are driven mainly by the germline-encoded Vδ1 residues while TCR-β mediates specific lipid recognition (PDB: 4WO4) . (e) The γδ TCR recognizes CD1d–lipid complexes. Germline-encoded Vδ1 residues are responsible for CD1d binding while the lipid ligand recognition is fine-tuned by hypervariable complementarity-determining region (CDR) 3 loops (PDB: 4MNG) . (f) A mouse γδ TCR binds the MHC-like molecule T22. The binding occurs predominantly via a conserved motif within the hypervariable CDR3δ loop, whereas the non-conserved CDR3δ residues fine-tune the affinity of the receptor towards T22 (PDB: 1YPZ) .
Figure 12
Figure 12
The versatility of the human T cell receptor (TCR). The αβ TCR can engage intermediates in riboflavin biosynthesis in the context of MR1 and a variety of lipid molecules bound to CD1a, CD1b, CD1c and CD1d. Classically, this receptor is also capable of binding to the almost infinite array of different peptides bound to more than 12 000 human leucocyte antigen (HLA) alleles of the HLA-A, -B, -C, -DR, -DQ and -DP loci. γδ TCRs can also bind to CD1d-lipid complexes , and a variety of ectopically expressed cell stress markers including endothelial protein C receptor (EPCR) (shown), MIC A/B and hMSH2 . Murine γδ TCRs bind to the MHC-I like molecules T10 and T22 that are not found in humans . The best-studied set of human γδ T cells express Vγ9Vδ2 TCRs and recognize pyrophosphate antigens in the context of an immunoglobulin-like molecule, butyrophillin 3A1 . The exact mechanism by which these TCRs recognize phosphoantigens awaits a TCR-ligand structure.

Similar articles

See all similar articles

Cited by 15 articles

See all "Cited by" articles

References

    1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974;248:701–2. - PubMed
    1. Treiner E, Duban L, Bahram S, et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature. 2003;422:164–9. - PubMed
    1. Le Bourhis L, Martin E, Peguillet I, et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol. 2010;11:701–8. - PubMed
    1. Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature. 1994;372:691–4. - PubMed
    1. Van Rhijn I, Kasmar A, de Jong A, et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat Immunol. 2014;14:706–13. - PMC - PubMed

Publication types

MeSH terms

Substances

Feedback