The MHC locus contains two types of polymorphic MHC genes, the MHC-I and MHC-II genes, which encode two groups of structurally distinct but homologous proteins and other non polymorphic genes whose products are involved in antigen presentation (Fig. 1). The MHC-I and MHC-II molecules are the ones whose function is to display peptide antigens for recognition by CD8+ and CD4+ T cells, respectively. The nonpolymorphic molecules encoded in the MHC do not present peptides for T-cell recognition.

Fig1. Schematic maps of human and mouse major histocompatibility complex (MHC) loci. The basic organization of the genes in the MHC locus is similar in humans and mice. Sizes of genes and intervening DNA segments are not shown to scale. Class II loci are shown as single blocks, but each locus consists of several genes. HLA, Human leukocyte antigen; LT, lymphotoxin; TAP, transporter associated with antigen processing; TNF, tumor necrosis factor.

Different human HLA class I molecules were first distinguished by serologic approaches (antibody binding). Different MHC-II molecules were identified by use of assays in which T cells from one individual would be activated by cells of another individual (called the mixed lymphocyte reaction). Currently, DNA sequencing is used to distinguish different MHC alleles in the population.

MHC-I and MHC-II genes are the most polymorphic genes present in mammalian genomes. Among all humans, the total number of HLA alleles with different amino acid sequences is estimated to be over 13,000, with more than 3500 variants for the HLA-B locus alone and over 6000 alleles of class II genes. The variations in MHC molecules (accounting for their poly morphism) result from inheritance of distinct DNA sequences and are not induced by somatic gene recombination (as they are in antigen receptors). Because the products of different MHC alleles bind and display different peptides, different individuals in a population may present different peptides even from the same protein antigen.

The high degree of polymorphism of the MHC helps to protect mammalian populations from a virtually unlimited diversity of microbes and therefore prevents loss of entire populations from emerging infections. In other words, because of the preservation of a large number of different MHC molecules in the population, there will almost always be individuals able to present peptides from almost any microbe to their T cells. The evolution of new MHC alleles occurs by a mechanism called gene conversion, which involves copying the nucleotide sequences from one allele to another during meiosis.

MHC genes are codominantly expressed in each individual. Thus, for a given MHC gene, each individual expresses the alleles that are inherited from both parents. For the individual, this maximizes the number of MHC molecules available to bind peptides for presentation to T cells.

Human and Mouse MHC Gene Loci

In humans the MHC is located on the short arm of chromo some 6 and occupies a large segment of DNA, extending about 3500 kilobases (kb). In classical genetic terms, the MHC locus extends about 4 centimorgans, meaning that crossovers within the MHC occur in about 4% of meioses. A molecular map of the human MHC is shown in Fig.2.

Fig2. Map of the human major histocompatibility complex (MHC). The genes located within the human MHC locus are illustrated. In addition to the MHC class I and class II genes, HLA-E, HLA-F, and HLA-G and the MIC genes encode class I–like molecules, many of which are recognized by natural killer cells. C4, C2, and factor B are complement proteins; tapasin, DM, DO, TAP, and proteasome subunits are proteins involved in antigen processing, discussed later in the chapter; lymphotoxin α (LTα), LTβ, and tumor necrosis factor (TNF) are cytokines. Many pseudogenes and genes whose roles in immune responses are not established are located in the HLA complex but are not shown to simplify the map. HLA, Human leukocyte antigen; TAP, transporter associated with antigen processing.

Three MHC-I genes called HLA-A, HLA-B, and HLA-C  encode three types of MHC-I molecules with the same names. There are three HLA class II gene loci called HLA-DP, HLA-DQ, and HLA-DR. Each MHC-II molecule is composed of a het erodimer of α and β polypeptides. The DP, DQ, and DR loci on each chromosome contain separate genes designated A and B, encoding the α and β chains, respectively. The nomenclature of the HLA locus takes into account the enormous polymorphism identified by serologic and molecular methods. Thus, based on modern molecular typing, individual alleles may be called HLA-A*0201, referring to the 01 subtype of HLA-A2, or HLA DRB1*0401, referring to the 01 subtype of the DR4B1 gene, and so on.

The mouse MHC, located on chromosome 17, occupies about 2000 kb of DNA, and the genes are organized in an order slightly different from those in the human MHC. One of the mouse class I genes (H-2K) is centromeric to the class II region, but the other class I genes are telomeric to the class II region. There are three mouse MHC-I genes called H-2K, H-2D, and H-2L, encoding three different MHC-I proteins, K, D, and L. These genes are homologous to the human HLA class I genes. The MHC alleles of particular inbred strains of mice are designated by lowercase letters (e.g., a, b), named for the whole set of MHC genes of the mouse strain in which they were first identified. In the parlance of mouse geneticists, the allele of the H-2K gene in a strain with the k-type MHC is called Kk (pronounced K of k), whereas the allele of the H-2K gene in a strain with d-type MHC is called K^d (K of d). Similar terminology is used for H-2D and H-2L alleles. Mice have two MHC-II loci called I-A and I E, which encode the I-A and I-E molecules, respectively. These loci are the Ir genes discussed earlier. The mouse class II genes are homologous to human HLA-DP, DQ, and DR genes. The I-A allele found in the inbred mouse strain with the Kk and Dk alleles is called I-Ak (pronounced IA of k). Similar terminology is used for the I-E allele. As in humans, there are actually two different genes, designated A and B, in the I-A and I-E loci that encode the α and β chains of each MHC-II molecule.

The set of MHC alleles present on each chromosome is called an MHC haplotype. For instance, an HLA haplotype of an individual could be HLA-A24, B35, C3, DRB12, DPB1 DQB3, and so on (using the simpler nomenclature for HLA alleles). All heterozygous individuals, of course, have two HLA haplotypes. Inbred mice, being homozygous, have a single haplotype. Thus, the haplotype of an H-2^d mouse is H-2K^d I-A^d I-E^d D^d L^d. The MHC genes are tightly linked, so that haplotypes are inherited en bloc, and individuals will usually express all of the MHC alleles in the two haplotypes inherited from their parents.

Expression of MHC Molecules

 Because MHC molecules are required for presentation of anti gens to T lymphocytes, the expression of these proteins in a cell determines whether foreign (e.g., microbial) antigens in that cell will be recognized by T cells. There are several important features of the expression of MHC molecules that contribute to their role in protecting individuals from different microbial infections.

MHC-I molecules are expressed on virtually all nucleated cells, whereas MHC-II molecules are expressed only on DCs, B lymphocytes, macrophages, thymic epithelial cells, and a few other cell types. This pattern of MHC expression is linked to the functions of class I–restricted CD8+ and class II–restricted CD4+ T cells. As discussed earlier, CD8+ CTLs kill cells infected with intracellular microbes, such as viruses, as well as tumors that express tumor antigens, and any nucleated cell can harbor a virus or undergo malignant transformation. Thus, the expression of MHC-I molecules on nucleated cells provides a display system for viral and tumor antigens, so these antigens can be recognized by CTLs and the cells containing the antigens can be killed. In contrast, class II–restricted CD4+ helper T lymphocytes have a set of functions that require recognizing antigen presented by a more limited number of cell types, and MHC-II molecules are expressed mainly on these cell types. Differentiated CD4+ helper T lymphocytes function mainly to activate (or help) macrophages and recruit neutrophils to eliminate extracellular microbes that are phagocytosed by macrophages and to help B lymphocytes make antibodies that also eliminate extracellular microbes. In order to initiate an immune response, naive CD4+ and CD8+ T cells need to recognize antigens that are captured and presented by DCs in lymphoid organs, which express both class I and class II MHC molecules. Thymic epithelial cells also express both class I and class II molecules, and antigen display by these cells is important in the process of selection of maturing CD4+ and CD8+ T lymphocytes.

The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses. Although MHC-I molecules are constitutively expressed on nucleated cells, their expression is increased by the type I IFNs, IFN-α and IFN-β, which are produced during the early innate immune response to many viruses. Thus, innate immune responses to viruses increase the expression of the MHC molecules that display viral antigens to virus-specific T cells. This is one of the mechanisms by which innate immunity stimulates adaptive immune responses. The expression of class I molecules is also increased by IFN-γ.

The expression of MHC-II molecules is regulated by cytokines and other signals in different cells. IFN-γ is the principal cytokine involved in stimulating expression of class II molecules in APCs such as DCs and macrophages (Fig. 3). IFN-γ may be produced by natural killer (NK) cells during early innate immune reactions and by antigen-activated T cells during later adaptive immune reactions. Thus, the ability of IFN-γ to increase MHC-II expression provides a mechanism by which innate immunity promotes adaptive immunity and also an amplification mechanism in adaptive immunity. B lymphocytes constitutively express class II molecules and can increase expression in response to antigen recognition and cytokines produced by helper T cells, thus enhancing antigen presentation to helper cells. IFN-γ can also increase the expression of MHC molecules on vascular endothelial cells and other nonimmune cell types; the role of these cells in anti gen presentation to T lymphocytes is unclear, as mentioned earlier. Some cells, such as neurons, never appear to express MHC-II molecules. After activation, human but not mouse T cells express MHC-II molecules; however, no cytokine has been identified in this response and its functional significance is unknown.

Fig3. Enhancement of class II major histocompatibility complex (MHC) molecule expression by interferon-γ (IFN-γ). IFN-γ, produced by natural killer (NK) cells and other cell types during innate immune reactions to microbes or by T cells during adaptive immune reactions, stimulates MHC class II expression on antigen-presenting cells (APCs) and thus enhances the activation of CD4+ T cells. IFN-γ and type I IFNs have a similar effect on the expression of class I MHC molecules and the activation of CD8+ T cells.

The amount of transcription is the major determinant of the level of MHC molecule synthesis and expression on the cell surface. Cytokines enhance MHC expression by stimulating the transcription of class I and class II genes in a wide variety of cell types. These effects are mediated by the binding of cytokine-activated transcription factors to DNA sequences in the promoter regions of MHC genes. Several transcription factors may be assembled and bind a protein called the class II transcription activator (CIITA). The entire complex binds to the class II promoter and promotes efficient transcription of the gene. By keeping the complex of transcription factors together, CIITA functions as a master regulator of class II gene expression. Mutations in CIITA or the associated transcription factors have been identified as the cause of human immunodeficiency diseases associated with defective expression of MHC molecules. The best studied of these disorders is bare lymphocyte syndrome. Knockout mice lacking CIITA also show reduced or absent MHC-II expression on DCs and B lymphocytes and an inability of IFN-γ to induce MHC-II on all cell types.

The expression of many of the proteins involved in anti gen processing and presentation is coordinately regulated. For instance, IFN-γ increases the transcription not only of class I and class II genes but also of several genes whose products are required for MHC-I assembly and peptide display, such as genes encoding the transporter associated with antigen processing (TAP) and some of the subunits of proteasomes, discussed later in this chapter.

In addition to transcriptional regulation, the level of MHC molecule expression is controlled by the level of ubiquitination dependent degradation, discussed later in the context of antigen processing.

اخر الاخبار

اخبار العتبة العباسية المقدسة

دار علوم نهج البلاغة تقيم محفلها الأسبوعي في بغداد

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"علكة مبتكرة" تستهدف ميكروبات الفم المسببة للسرطان

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الآخبار التكنلوجية

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تيم كوك ينهي 15 عاما في قيادة "أبل"

المزيد

مواضيع ذات صلة

Cytokine-Producing Innate Lymphoid Cells

Epithelial Barriers

C-Type Lectins: Receptors for Microbial Carbohydrates

Antigen Capture and the Functions of Antigen-Presenting Cells

Cytosolic DNA Sensors and the STING Pathway

RIG-Like Receptors

Inflammasomes

Antigens

NOD-Like Receptors: NOD1 and NOD2

Recognition of Microbes and Damaged Tissue by the Innate Immune System

Overview of Innate Immunity

Transplantation of Tissues and Organs