T‐Cell Antigen Recognition – Lessons from the Past and Projections into the Future


T‐cells are central to adaptive immunity and arguably to this date the most intensely studied cells in life sciences. Paying tribute to their developmental plasticity and the complexities associated with many of their physiological functions, numerous aspects of their physiology are still far from being understood to an extent that would be sufficient to rationally design therapies effectively targeting allergies, autoimmunity and cancer. T‐cell antigen recognition is no exception: this field took up speed with the rise of monoclonal antibodies and the first successful cloning of the T‐cell antigen receptor (TCR) genes roughly 40 years ago. In the meantime, hundreds of TCRs have been crystallised in complex with their nominal peptide/MHC (pMHC) binding partners and many TCR‐pMHC interaction kinetics have been measured. Furthermore most, if not all signalling molecules acting downstream of the TCR have been identified. Despite these accomplishments, we are still searching for convincing explanations as to how T‐cells mange to reliably detect the presence of even a single antigen on the surface of antigen‐presenting cells (APCs). Elaborating underlying mechanisms will invariably require a more advanced understanding of the molecular, subcellular and cellular context in which T‐cell antigen recognition operates. What renders this endeavour both challenging and exciting is the rather weak strength and promiscuous nature of TCR‐pMHC binding and the fact that antigenic pMHCs are typically vastly outnumbered on APC surfaces by structurally similar, yet nonstimulatory pMHCs. While research of the last 20 years has provided some clarity, it has also caused at times controversies, which need to be resolved to unleash the full potential that T‐cells offer for clinical progress.

Key Concepts

  • T‐cells are indispensable for orchestrating and executing cellular and humoral adaptive immune responses; in recurrent communication with other cells of the immune system, T‐cells continuously patrol our body in search for antigenic peptide fragments derived from pathogens or cancer‐derived neoantigens.
  • T‐cells are exquisitely sensitive for their nominal antigen as they can detect the presence of even a single stimulatory pMHC amongst thousands of structurally similar yet nonstimulatory pMHCs on the very crowded surface of an APC.
  • Despite considerable progress in the field over the last 40 years, the molecular, biophysical and (sub‐) cellular principles underlying the detection efficiency associated with T‐cell antigen recognition and are far from being resolved.
  • Given the complexities inherent to processes associated with T‐cell antigen recognition, which involve (1) the short‐lived nature of key protein–protein and protein–lipid interactions and (2) mechanical forces acting within the narrow confines of the immunological synapse, we consider integrative approaches combining classical biochemistry, structural biology and genetics with biophysics, advanced live‐cell imaging and systems biology most likely to provide much‐needed answers to most fundamental questions.
  • Easy access to both experimental/analysis modalities and primary data of published work as well as improved literacy in the areas of biophysics and systems biology will help accelerate progress in the field of T‐cell antigen recognition with immediate and far‐reaching clinical implications benefiting allergy, autoimmune and cancer patients.

Keywords: TCR; MHC; T‐cell antigen recognition; immunological synapse; T‐cell activation

Figure 1. Molecular determinants of T‐cell antigen recognition. (a) CD4+ T‐cells recognise antigenic peptides predominantly derived from extracellular space and presented on the surface of professional antigen‐presenting cells (APCs) in the context of MHCII molecules (left). The peptide‐binding groove of MHCIIs is assembled from a single α and a single β chain folding into two domains; the peptide‐binding domain (α1 and β1) is open on both sites and can accommodate large peptides (∼10–100 amino acids). TCRs of CD4+ T‐cells engage stimulatory peptides in concert with the CD4 co‐receptor, which binds to the β2 domain of MHCII. In contrast, CD8+ T‐cells detect antigenic peptides processed from intracellular proteins and presented via MHCI on all nucleated cells (right). The peptide binding cleft of MHCI is composed of two α helices (α1 and α2 domain) located on top of a β‐sheet platform and provides space for a small peptide no longer than 8–11 amino acids. TCRs of CD8+ T‐cells engage stimulatory pMHCI together with the αβCD8 co‐receptor; the CD8α chain binds to the α3 domain of MHCI. (b) Structural model of the extracellular part of the TCR‐CD3 complex. The illustration represents the extracellular domains of the CD3ϵγ (PDB: 1SY6) and CD3ϵδ heterodimers (PDB: 1XIW) in no specific arrangement or orientation with regard to the TCR constant domains (Cα and Cβ) or TCR variable domains (Vα and Vβ) of the human TCR 1E6 (PDB: 3UTP). Adapted from Natarajan et al. . (c) The quaternary assembly of the antigen‐binding TCRαβ heterodimer and the signal‐transducing CD3 subunits is mediated by intramembrane negatively (marked in blue) and positively (marked in red) charged amino acid residues and contacts between extracellular domains. The disulfide‐linked TCRαβ heterodimer is non covalently associated with CD3ϵδ, CD3ϵγ and the disulfide‐linked CD3ζ2 homodimer. Dimer‐formation with CD3γ and CD3δ is required for proper folding of CD3ϵ. Adapted from Call and Wucherpfennig .
Figure 2. TCR‐pMHC crystal structure and binding geometry. (a, b) Crystal structure of the murine TCR 226 binding to (H2‐Ek) I‐Ek in complex with the moth cytochrome c (MCC) peptide 92‐104 (ADLIAYLKQATKG) (PDB: 3QIU). The TCRα chain is coloured in blue; the TCRβ chain is illustrated in cyan. I‐Ek α (β) chain is depicted in (dark) grey and the MCC peptide in red. Variable and constant regions of the TCR are indicated. (b) An enlarged view of the TCR‐pMHC interaction shown in (a). The CDR1 and CDR2 loops of the variable TCRα (blue) and TCRβ chain (cyan) interact with conserved regions of the MHCβ1 domain (dark grey) and MHCα1 domain (grey), respectively; the hypervariable CDR3α and β regions interact predominantly with the presented peptide (MCC). (c) CDR footprint polarity of TCRs engaging H2‐Ak (I‐Ak) in five different TCR‐pMHC complexes. PDB accession numbers: 1U3H (red), 2Z31 (green), 2PXY (cyan), 1D9K (orange), 3C60 (violet). (d) The codon hypothesis for TCR‐pMHC engagement as proposed by Garcia et al., . Garcia et al. . Reproduced with permission of Springer Nature. The variable domains of the TCR (Vαβ) bind to different MHCs (W, X, Y) in a unique yet highly‐specific fashion using so‐termed interaction codons, which are shared by various MHC molecules. (e) According to the codon hypothesis, a single TCR can engage the very same MHC (MHC‐Z) in complex with different peptides by adapting to different interaction codons (A, B, C), which are in particular shaped by the CDR3 regions recognising the MHC‐bound peptide interface. The TCR is using altered docking footprints to bind the peptide within the MHC complex. The graph shows that each footprint denotes a low‐energy binding solution rather than an energetic continuum.
Figure 3. Overview of a mature immunological T‐cell synapse. (a) Schematic outline of an immunological synapse formed between a T‐cell and an APC. T‐cell surface receptors and signalling molecules promoting (blue) and inhibiting (red) T‐cell activation are indicated. Molecules expressed on the APC surface are illustrated in pink. (b) Antigen‐experienced 5c.c7 TCR‐transgenic CD4+ T‐cells were stained at their TCRβ chain with AF555‐H57 scFV (green) and allowed to make contact with a planar glass‐supported lipid bilayer (PLB) acting as surrogate APC as it presents B7‐1 (not visible), ICAM‐1‐AF488 (cyan) and the nominal antigen I‐Ek/MCC‐AF647 (red). Micrographs reveal a bull's eye‐shaped of a mature immunological synapse. (c) Upright projection of a mature immunological synapse, which can be subdivided into four distinct regions; the exo and endo cSMAC, the pSMAC and the dSMAC. Important receptor–ligand pairs and signalling molecules enriched within these particular regions are indicated.
Figure 4. Measuring 2D TCR‐pMHC interaction kinetics in situ. (a) Scheme of a FRET‐based assay to quantify TCR‐pMHC interactions within the immunological synapse. As shown, a CD4+ T‐cell approaches a protein functionalised PLB acting as surrogate antigen‐presenting cell surface by displaying fluorescently‐labelled pMHCIIs (e.g. I‐Ek /MCC(C)‐Cy5) together with co‐stimulator molecules (B7‐1) and adhesion factors (ICAM‐1). The combined crystallographic structure shows a site‐specifically Cy3‐conjugated H57 scFV (FRET‐donor, brown) binding to the TCRβ chain (cyan) that is in close enough proximity (4.1 nm, dashed line) to a site‐specifically Cy5‐conjugated peptide (MCC(C)‐Cy5, red) in complex with I‐Ek (FRET acceptor, dark pink) to allow FRET measurements of TCR‐pMHC binding in situ using TIRF microscopy (Huppa et al., ). (b) Ensemble FRET experiment showing two antigen‐experienced 5c.c7 TCR‐transgenic T‐cells (stained at their TCRβ chain with Cy3‐H57 scFV – here termed J1‐Cy3) approaching a functionalised PLB, which presents ICAM‐1, B7‐1 and the agonist I‐Ek /MCC(C)‐Cy5 (upper two panels) or the nonbinder I‐Ek/MCC null(C)‐Cy5 (lower panel). TCR‐agonist pMHC binding was determined through FRET donor recovery after acceptor photobleaching and FRET sensitised emission in TIRF microscopy mode. Note that the loss of the intensity in the FRET acceptor channel (yellow) gave rise to an increase in intensity in the FRET donor channel (green) after FRET acceptor photobleaching. No FRET signal was detected for I‐Ek /MCC null(C)‐Cy5 as TCR‐ligand binding is absent. Scale bar: 5 μm. (c) Single‐molecule FRET experiment to record and quantify single TCR‐pMHC binding events within the immunological synapse. A highly abundant FRET donor channel (Cy3‐H57 scFV – here termed J1‐Cy3 – bound to TCRβ first image in row), a single‐molecule FRET acceptor channel (I‐Ek/MCC(C)‐Cy5, second image in row), the smFRET channel and an overlay of all channels are shown. Single TCR‐pMHC binding events always appear and disappear within one frame and overlay with respective FRET acceptor events (white arrows). The yellow arrows represent a single FRET event that overlays with more than one FRET acceptor event. The grey bars show intensity values in counts. Individual smFRET (TCR‐pMHC binding) events can be traced over time to determine the half‐life of the synaptic TCR‐pMHC interactions (left). (a, b, c) Huppa et al. . Reproduced with permission of Springer Nature. (d) Scheme of an adhesion frequency assay with a biomembrane force probe to determine 2D‐binding constants of TCR‐pMHC interactions in situ. A single T‐cell is aspirated with a micropipette and confronted with an aspirated red blood cell (RBC) alone or with a bead attached to the RBC. T‐cells are then allowed to engage CD8‐binding deficient pMHCI molecules, which are linked via biotin and streptavidin to the beads. When the T‐cell is retracted from the RBC (or bead), individual TCR‐pMHC binding events become visible as they deform the RBC. 2D‐interaction kinetics of single TCR‐pMHC interactions can be obtained by fitting the measured frequency of deformations. Adapted from Chesla et al. , Huang et al. . (e) 2D binding kinetics measured via the adhesion frequency assay and 3D on‐rates and lifetimes obtained from SPR measurements of the OT‐I transgenic TCR engaging various pMHCI molecules are shown. Huang et al. . Reproduced with permission of Springer Nature. (f–h) TCR‐pMHC binding kinetics were determined by changes in mobility between free and TCR‐bound pMHCIIs. (f) Schematic illustration of a 5c.c7 TCR‐transgenic T‐cell approaching a functionalised PLB displaying ICAM‐1, B7‐1 and the agonist pMHCII I‐Ek/MCC(C)‐Cy5 or ‐Atto488 for diffusion‐based measurements of TCR‐ligand binding lifetimes. (g) TCR‐pMHC binding lifetimes of 5c.c7 TCR‐transgenic T‐cells recognising I‐Ek/MCC(C)‐Cy5 as determined by Axmann et al. . Distribution of the diffusion constant of single I‐Ek/MCC(C)‐Cy5 molecules (present at a density of 30 molecules per μm2) recorded at 28 °C (left upper panel) and 37 °C (left lower panel) outside (dark solid line) and within the immunological synapse (grey line). TCR‐pMHC binding lifetimes (upper and lower right) were compared to Monte Carlo simulations (solid black line) with the following fixed parameters: Dbound = 0 μm2 s−1, Dfree = 0.52 μm2 s−1 (28 °C), and Dfree = 0.69 μm2 s−1 (37 °C). Xp/% = fraction of TCR‐bound pMHCIIs. τoff/s = lifetime. Grey colour contour represents the p‐value. Recordings were performed with an exposure time of 1 ms and at time intervals (tdelay) of 49 ms. Axmann et al. . Reproduced with permission of Elsevier. (h) At short exposure times (17.5 ms, upper image, left) I‐Ek/MCC(C)‐Atto488 were identified by O'Donoghue et al. as single fluorescent entities freely diffusing within the PLB (O'Donoghue et al., ). Recordings with a longer exposure time (500 ms, upper image, right) separated slowly diffusing and TCR‐bound I‐Ek/MCC(C)‐Atto488 from a fast diffusing I‐Ek/MCC(C)‐Atto488 fraction (blurred). The lower diagram represents the distribution of measured TCR‐pMHC binding lifetimes in synapses of 5c.c7 TCR‐transgenic T‐cells confronted with PLB‐associated I‐Ek/MCC(C)‐Atto488 (present at a density of 100 molecules per μm2) at 37 °C and calculated directly by O'Donoghue et al. . Fluorophore bleaching (grey points) of Atto488 was determined on cell‐free PLBs and corrected for. O'Donoghue et al. . Licensed under CC BY.
Figure 5. In situ analysis of synaptic forces exerted on the TCR‐pMHC bond. (a) Scheme of the biomembrane force probe to measure synaptic forces. A micropipette‐aspirated T‐cell is confronted with a bead attached to the apex of an RBC held in position by a pipette. The bead is covalently linked to single streptavidin and pMHCI molecules to be recognised by the TCR (upper image). Representative force trace of a TCR‐pMHC lifetime measurement. After adhesion with the probe bead, the T‐cell was loaded with a preset level of retraction force (here of about 7 pN) until dissociation (marked by a red star) to determine the lifetime of a single TCR‐pMHC bond. (b) Examples of OT‐I TCRs forming a catch bond (upper image) or a slip bond (lower image) with representative pMHCI complexes (peptides loaded onto H2‐Kb are indicated) and assayed using a the biomembrane force probe. TCR‐pMHC pairs forming a catch bond show higher lifetimes under force than TCR‐pMHC pairs forming a slip bond, which exhibit shorter lifetimes under force. Liu et al. . Reproduced with permission of Elsevier. (c) In order to trigger a calcium response in T‐cells, a vectoral piconewton force was applied either in the lateral (shear) or normal direction using an optical trap system (upper image). T‐cells were allowed to attach to a glass coverslip that was fixed to a piezoelectric stage. After a trapped pMHCI‐coated bead was guided to make contact with the T‐cell, an anisotropic force was exerted by moving the piezoelectric stage. ΔX indicates the displacement of the bead out of the trap centre (lower image). T‐cell triggering was dependent on pMHCI density and the direction of force. The diagram indicates VSV8 (vesicular stomatitis virus nuclear protein octapeptide) in complex with H2‐Kb, present at various densities on the bead with and without anisotropic forces applied to the T‐cell. The calcium response is indicated as a ratio of the maximum fluorescence intensity (Imax) and the initial fluorescence intensity (I0). Feng et al. . Reproduced with permission of National Academy of Sciences.


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Further Reading

Alcover A, Alarcon B and Di Bartolo V (2018) Cell biology of T cell receptor expression and regulation. Annual Review of Immunology 36: 103–125.

Dustin M and Depoil D (2011) New insights into the T cell synapse from single molecule techniques. Nature Reviews Immunology 11: 672–684.

Dustin ML (2014a) The immunological synapse. Cancer Immunology Research 2: 1023–1033.

Gaud G, Lesourne R and Love PE (2018) Regulatory mechanisms in T cell receptor signalling. Nature Reviews. Immunology 18: 485–497.

Huppa JB and Davis MM (2013) The interdisciplinary science of T‐cell recognition. Advances in Immunology 119: 1–50.

Rossjohn J, Gras S, Miles JJ, et al. (2015) T cell antigen receptor recognition of antigen‐presenting molecules. Annual Review of Immunology 33: 169–200.

Smith‐Garvin J, Koretzky G and Jordan M (2009) T cell activation. Annual Review of Immunology 27: 591–619.

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Platzer, René, and Huppa, Johannes B(Jan 2020) T‐Cell Antigen Recognition – Lessons from the Past and Projections into the Future. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001229.pub3]