The Tcell receptor

Each T-cell possesses approximately 30,000 antigen-specific T-cell receptor (TCR) molecules on its surface, each with the same antigen specificity. Unlike B-cell immunuoglobulin molecules, TCR is always surface-bound, is not secreted and does not undergo any form of isotype switching or somatic hypermutation. The TCR (Fig. 1.2) comprises two transmembrane glycoprotein chains, linked by a disulphide bond. A single a and a single p chain associate to form the majority (90%) of TCRs. However, 10% of T-cell TCRs are composed of a single 7 chain and a single 8 chain. The true functional significance of ap and 78 T-cells is unknown. Each TCR traverses the T-cell membrane, and the external part of each TCR chain consists of a V and a C domain, with the V region being highly polymorphic, and the single antigen-binding site is formed by the apposition of the two amino-terminal V regions. TCR antigen-specificity diversity is generated during T-cell maturation by random rearrangement of gene segments encoding the TCR Va and Vp regions. Rearrangement of the genes encoding the ap TCR produces an estimated 1015 variants, each with a different antigen specificity; 78 chain diversity is even greater, with an estimated 1018 specificities. In contrast to B-cells, T-cells are only able to recognize antigens displayed on cell surfaces. Infection of a cell by an intracellular pathogen is signalled by the surface expression of pathogen-derived peptide fragments, expressed in conjunction with glycoproteins encoded by the major histocom-patibility complex (MHC). It is the combination of pathogen peptide fragment bound to MHC molecule that is recognized by T-cells (Fremont et al., 1996).

Antigen-binding site a chain 0 chain

Antigen-binding site a chain 0 chain

Vß Variable region

C0 Constant region

Vß Variable region

C0 Constant region

T-cell membrane

Fig. 1.2. Schematic representation of a T-cell-receptor molecule. Each of the constituent a and p chains comprises a V and a C domain. The apposition of the two V (dark) domains forms the antigen-binding site of the molecule. The two chains are linked by a disulphide bond and anchored in the T-cell surface membrane.

The MHC (Germain, 1994; Huston, 1997)

The MHC is a large complex of genes that encode the major histocompatibility glycoproteins. These large cell-surface glycoproteins are present in some form on every nucleated cell and there are two structural variants (MHC class I and MHC class II). The MHC was originally identified and characterized by its profound influence on the rejection or acceptance of transplanted organs. The MHC is the molecular basis by which T-cells recognize intracellular pathogens in order to initiate or effect an immune response.

An MHC class I molecule (Fig. 1.3) consists of a highly polymorphic 44 kDa a chain that is non-covalently associated with a smaller non-polymorphic 12 kDa ^-microglobulin chain. The a chain spans the cell membrane and forms a cleft into which the pathogen-derived peptide fragment is inserted during assembly of the MHC molecule. An MHC class II molecule comprises a 34 kDa a chain and a 29 kDa (3 chain; both span the cell membrane (Fig. 1.4). Each chain is divided into two domains, with association of the a1 and p domains forming an open-ended peptide-binding cleft into which a processed antigen peptide fragment is incorporated. MHC class I molecules bind peptides of eight to ten amino acids that originate from pathogen proteins synthesized within the cell cytosol, typically from viruses and certain bacteria. MHC class II molecules bind peptides derived from pathogens that have been phagocytosed by macrophages or endocytosed by antigen-presenting cells' such as macrophages, B-cells and professional antigen-presenting cells. MHC-pathogen-peptide complexes are very stable and are expressed on the cell surface, ready for recognition by a T-cell with TCRs specific for the peptide-MHC complex; this is known as MHC restriction.

Peptide-binding cleft

  • microglobulin
  • microglobulin

Cell membrane

Fig. 1.3. Schematic representation of an MHC class I molecule. A single a chain is composed of three domains, a1, a2 and a3, and the apposition of the a1 and a2 domains forms the peptide-binding cleft. The a chain is non-covalently associated with a smaller non-polymorphic protein p2-microglobulin.

Peptide-binding cleft

0 chain

Peptide-binding cleft

0 chain

Cell membrane

Fig. 1.4. Schematic representation of an MHC class II molecule. Each of the constituent a and 0 chains comprises two domains. Apposition of the a1 and 01 domains forms the peptide-binding cleft.

T-cells expressing the CD8 antigen recognize peptides complexed with MHC class I molecules, which are expressed by all nucleated cells. The CD8 antigen is a surface molecule that acts as a co-receptor by simultaneously binding to the TCR and the MHC class I a3 domain. MHC class II-peptide complexes are recognized by T-cells expressing the CD4 antigen, which acts as a co-receptor (like CD8) by binding to the p2 domain of the MHC class II molecules already bound by TCR. In humans, approximately one-third of peripheral blood T-cells are CD8, two-thirds are CD4 and approximately 5-10% are CD4— CD8—, the functions of which are unclear.

The structure of the peptide-binding cleft determines the peptide-binding specificity of an MHC molecule, such that it binds to peptides with a broadly similar structure. There are several genetic organizational features of the MHC that result in nucleated cells expressing a highly polymorphic set of MHC molecules, each with differing peptide-binding specificities. The polymorphic nature of the MHC is the consequence of the MHC being formed by three major class I genes designated human leucocyte antigen (HLA)-A, HLA-B and HLA-C, and three main class II genes, HLA-DFJ HLA-DQ and HLA-DR; each of these loci is highly polymorphic. Furthermore, most individuals are heterozygous for MHC genes and there is co-dominant expression of the antigens coded by the maternally and paternally derived loci. Consequently, nearly all individuals express six class I and ten class II molecules, each with differing specificities. During an infection, it is highly likely that the proteins of a pathogen include peptide sequences that are recognized and presented to T-cells by at least one MHC molecule. The general explanation for MHC polymorphism is that it is an evolutionary response to pathogenic diversity, enabling the immune systems of individuals to respond to a wide range of existing and evolving pathogens. MHC polymorphism results in individuals with differing immunological capabilities to combat an individual pathogen, but on a population scale it is highly unlikely that any individual pathogen will be able to evade the immune system of every individual.

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