MHC Structure and Functions PDF

MHC – Structure and Functions Every mammalian species studied to date possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and non-self. The MHC partic...

MHC – Structure and Functions Every mammalian species studied to date possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and non-self. The MHC participates in the development of both humoral and cell mediated immune responses. While antibodies may react with antigens alone, most T cells recognize antigen only when it is combined with an MHC molecule. Furthermore, because MHC molecules act as antigen- presenting structures, the particular set of MHC molecules expressed by an individual influences the repertoire of antigens to which that individual’s T H and TC cells can respond. For this reason, the MHC partly determines the response of an individual to antigens of infectious organisms, and it The MHC is a collection of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans. The MHC is referred to as the HLA complex in humans and as the H-2 complex in mice. Although the arrangement of genes is somewhat different, in both cases the MHC genes are organized into regions encoding three classes of molecules. Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide antigens to TC cells. Class II MHC genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, DC and B cells), where they present processed antigenic peptides to TH cells. Class I and class II MHC molecules are membrane-bound glycoproteins that are closely related in both structure and function. Both types of membrane glycoproteins function as highly specialized antigen- presenting molecules that form unusually stable complexes with antigenic peptides, displaying them on the cell surface for recognition by T cells. In contrast, class III MHC molecules are a group of unrelated proteins that do not Class I MHC molecules encoded by the A, B, and C loci in humans and they are expressed in the widest range of cell types. These are referred to as classical class I molecules. Additional genes or groups of genes within the HLA complex also encode class I molecules; these genes are designated nonclassical class I genes. Expression of the nonclassical gene products is limited to certain specific cell types. Although functions are not known for all of these gene products, some may have highly specialized roles in immunity. For example, the expression of the class I HLA-G molecules on cytotrophoblasts at the fetal-maternal interface has been implicated in protection of the Class I MHC molecules contain a α chain associated noncovalently with a β2-microglobulin molecule. The chain is a transmembrane glycoprotein encoded by polymorphic genes within the A, B, and C regions of the human HLA complex. Structural analyses have revealed that the chain of class I MHC molecules is organized into 3 external domains (α1, α2, and α3), a transmembrane domain followed by a short stretch of charged (hydrophilic) amino acids; and a cytoplasmic anchor segment. The α1 and α2 domains interact forms a deep groove, or cleft. This peptide-binding cleft is located on the top surface of the class I MHC molecule, and it is large enough to bind a peptide of 8–10 amino acids. The α3 domain appears to be highly conserved among Class I MHC molecules bind peptides and present them to CD8 T cells. In general, these peptides are derived from endogenous intracellular proteins that are digested in the cytosol. The peptides are then transported from the cytosol into the cisternae of the endoplasmic reticulum, where they interact with class I MHC molecules. This process, known as the cytosolic or endogenous processing pathway. Each type of class I MHC molecule (A, B, and C in humans) binds a unique set of peptides. In addition, each allelic variant of a class I MHC molecule also binds a distinct set of peptides. Because a single nucleated cell expresses about 10 5 copies of each class I molecule, many different peptides In normal, healthy cells, the class I molecules will display self-peptides resulting from normal turnover of self proteins. In cells infected by a virus, viral peptides, as well as self peptides, will be displayed. Because of individual allelic differences in the peptide binding clefts of the class I MHC molecules, different In general, the classical class I MHC molecules are expressed on most nucleated cells, but the level of expression differs among different cell types. The highest levels of class I molecules are expressed by lymphocytes, where they constitute some 5×105 molecules per cell. In contrast, fibroblasts, muscle cells, liver hepatocytes, and neural cells express very low levels of class I MHC molecules. The low level on liver cells may contribute to the considerable success of liver transplants by reducing the likelihood of graft recognition by Tc of the recipient. The bound peptides isolated from different class I molecules have been found to have two distinguishing features: they are 8 to 10 amino acids in length, most commonly 9, and they contain specific amino acid residues that appear to be essential for binding to a particular MHC molecule. The ability of an individual class I MHC molecule to bind to a diverse spectrum of peptides is due to the presence of the same or similar amino acid residues at several defined positions along the peptides. Because these amino acid residues anchor the peptide into the groove of the MHC molecule, they are called anchor residues. Class II MHC molecules contain two different polypeptide chains, a α chain and a β chain, which associate by noncovalent interactions. Each chain in a class II molecule contains two external domains: α1 and α2 domains in one chain and β1 and β2 domains in the other. The membrane-distal portion of a class II molecule is composed of the α1 and β1 domains and forms the antigen binding cleft for processed antigen. Class I presents more of a socket, class II an Class II MHC molecules bind peptides and present these peptides to CD4 T cells. Like class I molecules, molecules of class II can bind a variety of peptides. In general, these peptides are derived from exogenous proteins (either self or nonself), which are degraded within the endocytic processing pathway. Most of the peptides associated with class II MHC molecules are derived from membrane bound proteins or proteins associated with the vesicles of the endocytic processing pathway. The membrane-bound proteins presumably are internalized by phagocytosis or by receptor- Unlike class I MHC molecules, class II molecules are expressed constitutively only by antigen-presenting cells, primarily macrophages, DC and B cells. Peptide binding studies and structural data for class II molecules indicate that a central core of 13 amino acids determines the ability of a peptide to bind class II. Longer peptides may be accommodated within the class II cleft, but the binding characteristics are determined by the central 13 residues. The peptides that bind to a particular class II molecule often have internal conserved “motifs,” but unlike class I–binding peptides, they lack conserved anchor residues. Instead, hydrogen bonds between the backbone of the peptide and the class II molecule are distributed throughout Whether an antigenic peptide associates with class I or with class II molecules is dictated by the mode of entry into the cell, either exogenous or endogenous, and by the site of processing. Antigen-presenting cells can internalize antigen by phagocytosis, endocytosis, or both. Macrophages internalize antigen by both processes, whereas B cells internalize Since APCs express both class I and class II MHC molecules, some mechanism must exist to prevent class II MHC molecules from binding to the same set of antigenic peptides as the class I molecules. When class II MHC molecule are synthesized within the RER, three pairs of class II αβ chains associate with a preassembled trimer of a protein called invariant chain (CD74). This trimeric protein interacts with the peptide-binding cleft of the class II molecules, preventing any endogenously derived peptides from binding to the cleft while the class II Most class II MHC–invariant chain complexes are transported from the RER, where they are formed, through the golgi complex, and then through the endocytic pathway, moving from early endosomes to late endosomes, and finally to lysosomes. As the proteolytic activity increases in each successive compartment, the invariant chain is gradually degraded. However, a short fragment of the invariant chain termed CLIP (for class II–associated invariant chain peptide) remains bound to CLIP physically occupies the peptide- binding groove of the class II MHC molecule, presumably preventing any premature binding of antigenic peptide. HLA-DM, a nonclassical MHC class II molecule expressed within endosomal compartments, mediates exchange of antigenic peptides for CLIP. The nonclassical class II molecule HLA- DO may act as a negative regulator of class II antigen processing by binding to Several hundred different allelic variants of class I and II MHC molecules have been identified in humans. Any one individual, however, expresses only a small number of these molecules— up to 6 different class I molecules and up to 12 different class II molecules. Yet this limited number of MHC molecules must be able to present an enormous array of different antigenic peptides to T cells, permitting the immune system to The number of amino acid differences between MHC alleles can be quite significant, with up to 20 amino acid residues contributing to the unique structural nature of each allele. Thus, peptide binding by class I and II molecules does not exhibit the fine specificity characteristic of antigen binding by antibodies and T-cell receptors. Instead, a given MHC molecule can bind numerous different peptides, and some Antibodies and T-cell receptors are generated by several somatic processes, including gene rearrangement and somatic mutation of rearranged genes. Thus, the generation of T and B cell receptors is dynamic, changing over time within an individual. By contrast, the MHC molecules expressed by an individual are fixed in the genes and do not change over time. The diversity of the MHC within a species stems from polymorphism, the presence of multiple alleles at a given genetic locus within the species. Diversity of MHC molecules in an individual results not only from having different alleles of each gene but also from the presence of duplicated genes with similar or overlapping functions. Because it includes The loci constituting the MHC are highly polymorphic. The genes of the MHC loci lie close together; for example, the recombination frequency within the H-2 complex (i.e., the frequency of chromosome crossover events during mitosis, indicative of the distance between given gene segments) is only 0.5%— crossover occurs only once in every 200 mitotic cycles. For this reason, most individuals inherit the alleles encoded by these closely linked loci An individual inherits one haplotype from the mother and one haplotype from the father. In outbred populations, the offspring are generally heterozygous at many loci and will express both maternal and paternal MHC alleles. The alleles are codominantly expressed; that is, both maternal and paternal gene products are expressed in the same cells. Because such an F1 expresses the MHC proteins of both parental strains on its cells, it is histocompatible with both strains and able to accept grafts from either parental strain. However, neither of the inbred parental strains can Although the rate of recombination by crossover is low within the HLA, it still contributes significantly to the diversity of the loci in human populations. Genetic recombination generates new allelic combinations, and the high number of intervening generations since the appearance of humans as a species has allowed extensive recombination, so that it is rare for any two unrelated