Class I MHC

Figure 15.18 (a) Schematic representation of the path of the polypeptide chain in the structure of the class I MHC protein HLA-A2. Disulfide bonds are indicated as two connected spheres. The molecule is shown with the membrane proximal immunoglobulin-like domains (a3 and Pzm) at the bottom and the polymorphic al and a2 domains at the top. 

Figure 15.19 Schematic representation of the peptide-binding domain of a class I MHC protein. The al and a2 domains are viewed from the top of the molecule, showing the empty antigen-binding site as well as the surface that is contacted by a T-cell receptor. (Adapted from P.J. Bjdrkman et al.. Nature 329 506-512, 1987.)...

The genes for MHC molecules, unlike immunoglobulin genes, do not undergo rearrangements to create structural diversity. The Pzm light chain is invariant, but the class I MHC heavy chain is the most genetically polymorphic... 

Most transformed cells do not express class II MHC molecules and express lower than normal levels of class I MHC molecules. This renders their detection by immune effector cells more difficult. Treatment with cytokines, such as IFN-y, can induce increased class I MHC expression, which normally promotes increased tumour cell susceptibility to immune destruction. 

Class I MHC proteins occur in almost all nucleated cells. They mainly interact with cytotoxic T cells and are the reason for the rejection of transplanted organs. Class 1 MHC proteins are heterodimers (a 3). The p subunit is also known as P2-microglobulin. 

The illustration shows an interaction between a virus-infected body cell (bottom) and a CD8-carrying cytotoxic T lymphocyte (top). The infected cell breaks down viral proteins in its cytoplasm (1) and transports the peptide fragments into the endoplasmic reticulum with the help of a special transporter (TAP) (2). Newly synthesized class I MHC proteins on the endoplasmic reticulum are loaded with one of the peptides (3) and then transferred to the cell surface by vesicular transport (4). The viral peptides are bound on the surface of the a2 domain of the MHC protein in a depression formed by an insertion as a floor and two helices as walls (see smaller illustration). 

These proteins consist of a and /3 chains, (a) In class I MHC proteins, the small /3 chain is invariant but the amino acid sequence of the a chain exhibits a high degree of variability, localized in specific domains of the protein that appear on the outside of the cell. Each human produces up to six different a chains for class I MHC proteins, (b) In class II MHC proteins, both the a and /3 chains have regions of relatively high variability near their amino-terminal ends. 

Class II MHC proteins occur on the surfaces of a few types of specialized cells, including macrophages and B lymphocytes that take up foreign antigens. Like class I MHC proteins, the class II proteins are highly polymorphic, with many variants in the human popula-... 

F1GURE 5-22 Structure of a human class I MHC protein, (a) This model is derived in part from the known structure of the extracellular portion of the protein (PDB ID 1 DDH). The a chain of MHC is shown in gray the small /3 chain is blue the disulfide bonds are yellow. A bound ligand, a peptide derived from HIV, is shown in red. (b) Top view of the protein, showing a surface contour image of the site where peptides are bound and displayed. The HIV peptide (red) occupies the site. This part of the class I MHC protein interacts with T-cell receptors. 

Ubiquitin-dependent proteolysis is as important for the regulation of cellular processes as for the elimination of defective proteins. Many proteins required at only one stage of the eukaryotic cell cycle are rapidly degraded by the ubiquitin-dependent pathway after completing their function. The same pathway also processes and presents class I MHC antigens (see Fig. 5-22). Ubiquitin-dependent destruction of cyclinis critical to cell-cycle regulation (see Fig. 12-44). The E2 and E3 components of the ubiquitination cascade pathway... 

The two classes of MHC proteins are displayed on different cell types. Class I MHC proteins are found on almost all nucleated cells, including killer T cells. Class II MHC proteins are found mainly on cells involved in the immune response, including antigen-presenting cells, B cells, and T helper cells, but not T killer cells. 

Key words scid, Rag, humanized mice, GVHD, immunodeficient mice, MHC class I, MHC... 

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