Epitopes

Abstract

T and B lymphocytes, the mediators of adaptive immune responses, express antigen‐specific receptors that allow them to discriminate between self and a virtually unlimited number of nonself molecules. Their receptors specifically recognise and bind subdomains of foreign macromolecules which are called epitopes. T‐cell epitopes (TCEs) and B‐cell epitopes (BCEs) differ fundamentally in the way they are recognised by the immune system. BCEs are recognised as three‐dimensional structures on the surface of native antigens. TCEs are parts of internalised and processed antigens that are presented to T lymphocytes in association with molecules of the major histocompatibility complex. As in a biological system T‐ and B‐cell receptors or antibody molecules face a virtual infinite number of structures, cognate interactions with epitopes are the basis of the primordial intelligence that drives the teleological choices of the immune system. Immunodominance directs the immune response towards selected epitopes.

Key Concepts

  • Surface immunoglobulins of B cells and antibodies recognise the B‐cell epitope (BCE) of an antigen in its native conformation, while T‐cell receptors (TCRs) recognise the T‐cell epitopes (TCEs) only after intracellular processing of the antigen, and in association with major histocompatibility complex (MHC) molecules.
  • The main common feature of B‐cell epitopes is accessibility on the surface of the antigen.
  • TCE peptides that bind to the same allele of MHC molecules share common ‘anchor’ residues (motifs) that contact the MHC molecule.
  • TCEs presented by MHC class II molecules are longer and more variable in size and their anchor residues are less well defined than those of peptides presented by MHC class I molecules.
  • Patterns of anchor residues facilitate the prediction of peptide binding to MHC molecules.
  • The TCR–MHC–peptide tripartite cognate interaction in concert with coreceptors and other signalling modules mediate T‐cell activation.
  • Immunodominance refers to the concept that only a small subset of the potential epitopes (TCEs or BCEs) present in a given antigen elicit an immune response.
  • Mimotopes are small molecules that mimic the structure of complex conformational epitopes without any sequence homology.
  • While TCEs can be predicted with some confidence, ill‐defined characteristic features of BCEs limit their predictability.
  • Epitope‐based vaccines will allow to better manage desired and undesired cross‐reactivity.

Keywords: epitope; major histocompatibility complex; T‐cell receptor; antibody; B‐cell receptor; antigen; MHC restriction; paratope

Figure 1. Antibody structure. (a) Three‐dimensional structure of an IgG antibody molecule (PDB ID: 1IGT). (b) Schematic representation of the IgG scaffold. The antibody is a Y‐shaped molecule that is composed of two different polypeptide chains, the heavy (H) and the light (L) chain. Each molecule contains two of each of these chains. The constant domain of the antibody (C) is responsible for effector functions, while the variable domain (V or Fv) is implicated in antigen recognition. The different chains of the antibody are linked by disulphide bonds. The variable domain of the antibody contains three hypervariable regions, called complementarity determining regions (CDRs), that form the antigen‐binding site (L1, L2 and L3 on the light chain and H1, H2 and H3 on the heavy chain). The less variable regions flanking the CDRs contain six framework regions (FRs). On the basis of the function of the different subunits, the antibody molecule is sometimes subdivided into two major fragments: class‐defining fragment (Fc) and antigen‐binding fragment (Fab). Reproduced by permission of Yanay Ofran © Sela‐Culang et al., 2013.
Figure 2. Antibody topography classes as proposed by Lee . in 2006. 1MFD: antibody ‘crater’ complexed with the trisaccharide: α‐d‐galactose(1‐2)[α‐d‐abequose(1‐3)]α‐d‐mannose (P1‐OMe), 1GAF: antibody ‘cave’ complexed with the hapten 5‐( ‐nitrophenyl phosphonate)‐pentanoic acid, 1BFV: antibody ‘canyon’ complexed with estriol 3‐(β‐d‐glucuronide), 1HH6: antibody ‘valley’ complexed with an epitope‐homologous peptide, 1NMB: antibody ‘plain’ complexed with a five‐residue linker and influenza virus neuraminidase. The structures shown (Lee ., ) illustrate different binding modes through which antibodies can recognise epitopes. PDB IDs are indicated next to each structure. Green: heavy chains, blue: light chains, red: Chothia complementarity determining regions, grey: other, pink: bound antigen chains. Reproduced from structural antibody database SAbDab (http://opig.stats.ox.ac.uk/webapps/sabdab) (Dunbar et al., 2014). Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/).
Figure 3. Predicted epitopes versus the actual epitopes of HEL. (a) The 3D structure of HEL (CPK representation) together with three antibodies (ribbon representation). PDB IDs 1JHL, 3D9A and 1MLC were superimposed according to HEL structure. Epitope residues involved in the binding to the different antibodies are colour coded. Residues that are common to two epitopes are shown in orange. (b) The structure of HEL as in (a), presented in a different orientation. (c) The structure of HEL with colour‐coded eptiopes predicted by Discotope (light blue), ElliPro (purple) and SEPPA (pink). Not all predicted residues of Discotope and ElliPro are shown. Reproduced by permission of Yanay Ofran © Sela‐Culang et al., 2013.
Figure 4. Ribbon diagrams (a,b) and space filling models (c,d) of the binding groove of MHC class I and II molecules. In MHC class I molecules (a,c), the whole peptide, including its ends, are buried within the peptide groove. In MHC class II molecules (b,d), the groove is open on both ends allowing the ‐ and ‐terminal ends of longer peptides to protrude. In (c) and (d), the positive and negative electrostatic potential of the MHC molecule is shown in blue and red. Reproduced by permission from Murphy KM, Travers P and Walport M (2007) © Garland Science/Taylor & Francis LLC.
Figure 5. TCR recognition of the peptide–MHC complex. Analysis of several TCR–MHC–peptide complexes showed a similar orientation of the TCR on top of the peptide–MHC complex. The CDRs of the T‐cell receptor, which are the most variable sites within the T‐cell receptor and have been implicated in peptide‐MHC recognition, are colour coded: the CDR1 and CDR2 loops of the β chain in light and dark blue, the CDR1 and CDR2 loops of the α chain in light and dark purple, the α chain CDR3 loop in yellow and the β chain CDR3 loop in green, the β chain HV4 loop in red. The thick yellow line P1–P8 is the MHC‐bound peptide. Reproduced by permission from Murphy KM, Travers P and Walport M (2007) © Garland Science/Taylor & Francis LLC.
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Further Reading

Apostopoulos V, Yuriev E, Lazoura E, Yu M and Ramsland PA (2008) MHC and MHC‐like molecules: structural perspectives on the design of molecular vaccines. Human Vaccines 4 (6): 400–409.

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Peters B and Sette A (2007) Integrating epitope data into the emerging web of biomedical knowledge resources. Nature Reviews Immunology 7 (6): 485–490.

Sela‐Culang I, Kunik V and Ofran Y (2013) The structural basis of antibody‐antigen recognition. Frontiers in Immunology 4: 302.

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How to Cite close
Kirpach, Josiane, and Muller, Claude P(Sep 2015) Epitopes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000514.pub3]