Specific Defenses of the Host Part 2 (acquired or adaptive immunity)

Mechanisms of the Immune Response, continued The MHC This is a region of highly polymorphic genes found, in humans, on chromosome 6. The products of the MHC are found on a variety of cell surfaces and are called histocompatibility antigens. The histocompatibility antigens function as peptide presenters. In humans these antigens are collectively called the Human Leukocyte Antigens (HLA) and they include three classes of genes.

Mechanisms of the Immune Response, continued Class I genes encode the class I histocompatibility antigens that are found on the surfaces of most nucleated cells. Class II genes encode the class II histocompatibility antigens that are found on cells involved in immune functions (B cells, macrophages, among others) Class III genes encode the complement components and other gene products that have various functions in the immune system.

The MHC Regions for Humans and Mice

Mechanisms of the Immune Response, continued All of the genes in the MHC are tightly linked and they are inherited as a block. Each allele at each locus is given a numerical designation and the total set of alleles on both chromosomes (1 from mom and 1 from dad) is called a haplotype. The corresponding alleles on the two chromosomes are co-dominant; i.e., both are expressed and they are equally functional. Individuals studying tissue transplant rejection first discovered the histocompatibility antigens. They are the principle determinants of tissue transplant rejections.

Mechanisms of the Immune Response, continued Their discovery led to an understanding of T cell restriction. T cells can only recognize foreign peptides if they are noncovalently bound to self-antigens, i.e., MHC molecules, from the same individual. The T cell receptor reacts with amino acid side chains from both the bound peptide and the MHC molecule itself. This explains why T cells cannot recognize antigens in a free or soluble form and why they only recognize linear peptides. The MHC molecule “presents” the antigenic determinant to the T lymphocyte.

Mechanisms of the Immune Response, continued How do the MHC class I molecules function? MHC class I antigens - Foreign antigens made within the cell (such as viral proteins) are bound to MHC class I antigens within the cells and move to the cell surface, where they stimulate cytotoxic (CD8+) T cells which act to destroy the cell displaying the foreign peptide. Both the binding of the T cell receptor to the MHC molecule and the bound peptide, and the binding of the CD8 molecule to the MHC molecule are required for T cell activation.

Presentation of Foreign Antigen Made within the cell to CD8+ T Cells TAP = transporter associated with antigen processing

Presentation of Foreign Antigen Made Within the cell to CD8+ T Cells

MHC Class I Interaction with CD8+ T Cell

Mechanisms of the Immune Response, continued In humans there are three functional class I loci, called A, B, and C. Assuming heterozygosity, every individual has six different class I molecules. These class I molecules participate in the destruction of virus infected cells and in graft rejection. The class I molecules consist of two separate polypeptide chains, alpha and beta. Only the alpha chain is MHC encoded. The alpha chain has four separate domains or regions: the peptide binding domain, the immunoglobulin-like domain, the transmembrane domain, and the cytoplasmic domain. The beta chain does not differ among individuals.

Structure of the MHC Class I Molecule

Mechanisms of the Immune Response, continued The peptide binding domain This region interacts with foreign peptides to form complexes that are recognized by CD8+ T cells. Two homologous segments called  1 and  2 interact to form an 8-stranded B pleated sheet and 2 supporting parallel strands of alpha helices which can bind peptides amino acids in length. Almost all of the polymorphic residues (the differences between different alleles) lie in the region where peptide binds. Other polymorphic residues are where the T cell receptor interacts with the MHC molecule itself. Differences here provide the basis for T cell restriction.

Polymorphism in the MHC Class I Molecule

Mechanisms of the Immune Response, continued Every MHC class I molecule can bind more than 1 different peptide. In terms of the peptides that each MHC class I molecule binds: All are 9-11 amino acids in length. All peptides that interact with a single allelic form of a class I molecule share common structural features. The shared features of the peptides that can bind to one allelic form of MHC class I molecules are different from the features shared by peptides that can bind to another allelic form. The term loose specificity is used to describe this phenomena. That is, each MHC molecule has loose specificity for its peptides. To summarize: each MHC class I molecule can bind many different peptides, but all the peptides that each binds have common structural features.

Mechanisms of the Immune Response, continued The extraordinary polymorphism within the MHC region that exists within the population protects the population, as a whole, from disease. A microorganism spreading through a population will have to adapt to each new host. It will not be able to mutate and therefore be resistant to everyone’s immune system. The immunoglobulin-like domain (alpha 3 region) This region is highly conserved among class I molecules and is homologous to the constant domain of immunoglobulin molecules. This is the region where the CD8 molecules on the surface of cytotoxic T cells interact with the MHC class I molecule.

Mechanisms of the Immune Response, continued The beta chain is invariant among all class I molecules and is also structurally similar to the immunoglobulin constant region. The beta chain interacts with the alpha 3 region and the alpha 1 and 2 regions in the beta sheet platform of the peptide binding domain. Peptide binding helps alpha and beta to fold properly and is required for transport of the MHC class I molecule to the cell surface. The transmembrane domain This domain consists of 25 hydrophobic residues in the form of an alpha helix.

Mechanisms of the Immune Response, continued The domain is terminated by basic residues. The transmembrane domain does not affect the extracellular conformation of the molecule. The cytoplasmic domain This domain consists of 30 amino acids at the COOH terminus of the protein. The sequence is not conserved, but it has conserved features. Its functional significance is unknown, but it has been suggested that it interacts with other membrane proteins and/or cytoskeletal proteins. In Summary:

Structure of the MHC Class I Molecule

Presentation of Foreign Antigen Made Within the cell to CD8+ T Cells

MHC Class I Interaction with CD8+ T Cell