Tcell receptors

T cells recognize peptides presented in association with MHC molecules. In humans, the MHC molecules are also known as human leucocyte antigens (HLAs) and there are two classes of MHC molecule. MHC class I molecules (Figure 20.2) are expressed by all nucleated cells except germ cells. They are not expressed by erythrocytes but are found on the surface of

Recognized by TCR of CD8 T cells

Peptide generally derived from protein produced within the cell

Recognized by TCR of CD4 T cells

Peptide generally derived from protein taken up by the cell

Peptide generally derived from protein produced within the cell

Class I MHC with bound peptide

Class I MHC with bound peptide

Peptide generally derived from protein taken up by the cell

Class II MHC with bound peptide

Class II MHC with bound peptide

Figure 20.2 T cells recognize peptides held in MHC molecules. A class I MHC molecule is depicted on the left and a class II MHC molecule on the right. Some of the protein produced within each cell is broken down to peptides, which are presented on the cell surface in the peptide-binding groove of MHC molecules, usually class I (Figure 20.3). Extracellular molecules are taken up by antigen-presenting cells, broken down within the cell and presented on the cell surface in the peptide-binding groove of MHC molecules, usually class II (Figure 20.3). There are three isotypes of class II molecules, known as DP, DQ and DR, and three main class I isotypes, A, B and C. All of these are encoded within the MHC gene complex at 6p21.3. The genes encoding the peptide-binding grooves of each of these isotypes show extraordinary variability within the human population - 'allelic polymorphism' (Figure 20.5). The range of peptides that can be held by different MHC molecules varies. Consequently, this polymorphism is reflected in differences between individuals in the ability to recognize specific peptides. Any one TCR will only recognize a particular peptide within a particular groove structure. P2-Microglobulin is a non-polymorphic Ig-like domain that is non-covalently associated with HLA class I MHC molecules; it stabilizes peptide binding and is essential for the expression of class I on the cell surface.

erythroblasts. The peptides seen by T cells in association with class I MHC molecules are, in most circumstances, derived from proteins produced from within the cell. This places MHC class I molecules in an excellent position to present peptides derived from viral proteins following intracellular viral infection (Figure 20.3). It is now clear that antigen-presenting cells are also able to take up proteins from outside the cell and process them such that peptides gain access to the MHC class I presentation. This process is called cross-presentation and may be particularly important in generating CD8+ T cell responses to tumour-associated proteins.

MHC class I antigen presentation starts with the intracellular breakdown of proteins by a multimolecular proteolytic complex known as a proteasome. These peptides are actively transported by TAP (transporter associated with antigen processing) proteins into the endoplasmic reticulum, where empty MHC class I molecules are being assembled. The nascent MHC molecules are able to 'fold' around the peptides, which make non-covalent interactions with the peptide-binding groove at the top of the molecule. This complex is then stabilized by the association of P2-microglobulin before being transported to the cell surface. In this way, the cells are continuously advertising the peptide composition of the proteins that they are producing.

The selection of T cells during their development in the thymus involves the processes of negative selection and positive selection. T cells that have high affinity for self-peptides held in the groove of a self MHC molecule are deleted by apoptosis in a process known as negative selection. T cells with lower affinity for self peptide-MHC complexes are positively selected and survive to become peripheral T cells. T cells that recognize peptide presented by MHC class I molecules express a molecule CD8, which binds to the a3 domain of the MHC class I molecule (Figure 20.4). When any cell in the body presents immunogenic peptides, these may be recognized by a cytotoxic CD8 T lymphocyte that can then kill the target cell. This is most likely to occur as the result of virus infection when virus-encoded proteins are produced; it may also occur following the acquisition of a genetic mutation within a cell.

The other class of MHC molecule, MHC class II (Figure 20.2), is less widely expressed. The only cells that constitutively express large amounts of this class of MHC molecule are: (i) specialized antigen-presenting cells collectively known as dendritic cells; (ii) B lymphocytes; and (iii) thymic epithelial cells. Dendritic cells are derived from haemopoietic stem cells and codevelop with monocytes; they can be derived from blood mononuclear preparations by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). They migrate to many tissues, particularly epithelia, where they remain until activated by local tissue injury. On activation, they take up fluid and particles from their surrounding environment (Figure 20.3).

The pinocytotic activity in these cells can be induced by IL-1 and tumour necrosis factor (TNF) released at sites of injury. The pinocytotic vesicles fuse with an antigen-presenting endosomal compartment; proteolytic enzymes within this compartment are activated and proteins are broken down to peptides by the action of lysosomal enzymes. Class II molecules with peptide-binding grooves sealed by invariant chain (CD74) are inserted into the endosome wall. The invariant chain is digested and this allows peptides within the compartment to associate with MHC class II molecules. The MHC class II-peptide complex is then taken to the cell surface.

The scrutiny of antigen-presenting cells by T cells starts when dendritic cells have moved from peripheral tissues to the T cell-rich areas of adjacent secondary lymphoid organs. In that site they are known as interdigitating dendritic cells (IDCs),

Class I molecules mainly present Peptides derived from proteins produced within the cell itself

Cell membrane

Endogenous antigen-processing compartment • with class I MHC

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