Chapter 7 Major Histocomptibility Complex (MHC)

exogenous and endogenous antigens Processing and presentation of exogenous and endogenous antigens

Antigenic peptides recognized by T cells form trimolecular complexes with a TCR and an MHC molecule Class I MHC Peptide CD8 TCR TC cell peptide

TCR and MHC-peptide TCR  peptide  MHC

MHC molecules act as antigen-presenting structure. 2. MHC molecules expressed by an individual influence the repertoire of antigens to which that individual’s TH cells and TC vells can respond. 3. MHC partly determines the response of an individual to antigens of infectious organisms. 4. MHC has been implicated in the susceptibility to disease and in the development of autoimmunity.

1. General Organization and Inheritance of the 本章大綱: 1. General Organization and Inheritance of the MHC 2. MHC Molecules and Genes 3. Genomic Map of MHC Genes 4. Cellular Distribution of MHC Molecules 5. Regulation of MHC Expression 6. MHC and Immune Responsiveness 7. MHC and Disease Susceptibility

General Organization and Inheritance of the MHC

Gorer (1930s): 1. Rejection of foreign tissue is the result of an immune response to cell-surface molecules. 2. Identification of I, II, III and IV groups of genes. Gorer and Snell (1940s & 1950s): 1. Antigens encoded by the genes in the group II took part in the rejection of transplanted tumors and other tissues. 2. Snell called these genes “histocompatibility genes” (currently called H-2 genes) 3. Snell was awarded the Nobel Prize in 1980.

Human MHC: human leukocyte antigen (HLA) Mouse MHC: H-2

Class I MHC: Class II MHC: Class III MHC: Expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide Ags to CD8+ T cells. Class II MHC: Expressed primarily on Ag-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to CD4+ T cells. Class III MHC: Generally encode various secreted proteins that have immune functions, including components of the complement system and molecules involved in inflammation.

The MHC loci are polymorphic: Many alternative forms of the gene, or alleles, exist at each locus. The MHC loci are closely linked. The recombination frequency within the H-2 complex is only 0.5%. Most individuals inherit the alleles encoded by these closely linked loci as two sets, one from each parent. Each set of alleles is referred to as a haplotype. The MHC alleles are codominantly expressed; that is, both maternal and paternal gene products are expressed in the same cells.

Inheritance of MHC haplotypes

Acceptance or rejection of skin grafts is controlled by the MHC type of the inbred mice

Inheritance of HLA haplotype in a hypothetical human family

Congenic MHC mouse strain - Inbred mouse strains are syngeneic or identical at all genetic loci. - Two strains are congenic if they are genetically identical except at a single locus or region. - Congenic strains can be produced by a series of crosses, backcrosses, and selections.

Production of congenic mouse strain Strain A.B Genetically identical to strain A except for the MHC locus or loci contributed by strain B.

Examples of recombinant congenic mouse strains generated during production of the B10.A strain from parental strain B10 (H-2b) and parental strain A (H-2a)

MHC Molecules and Genes

Class I molecule (45 kDa) (12 kDa)

Class II MHC molecule (33 kDa) (28 kDa)

Class I and class II molecules

Class I a chain, class II a, b chains and b2M are members of the Ig superfamily

3-D structure of the external domains of a human class I HLA molecule based on x-ray crystallographic analysis

Cleft: 25Å x 10Å x 11Å can bind a peptide of 8-10 a.a.

Superimposition of the peptide-binding cleft of class I and class II MHC molecules Red: HLA-A2 (Class I) blue: HLA-DR1 (Class II)

Organization of class I MHC gene = K

Organization of class II MHC gene = IAb IAb IAa = IAa

Peptide binding by MHC molecules Peptide binding by class I and class II molecules does not exhibit the fine specificity characteristic of Ag binding by Ab and TCR. A given MHC molecule can bind numerous different peptides, and some peptides can bind to several different MHC molecules. The binding between a peptide and an MHC molecule is often referred to as “promiscuous” (雜亂的).

Peptide-binding cleft is blocked at both ends in class I molecules 8 – 10 amino acid residues, most commonly 9

Peptide-binding cleft is open at both ends in class I molecules 13 – 18 amino acid residues

Binding affinity of MHC to peptides The association constant KD of the peptide-MHC molecule complex is approximately 10-6. The rate of association is low, but the rate of dissociation is even lower. Thus, the peptide-MHC molecule association is very stable under physiological conditions and most of the MHC molecules expressed on the membrane of a cell are associated with a peptide of self or nonself origin.

Class I MHC molecules bind peptides and present them to CD8+ T cells – cytosolic or endogenous processing pathway

Anchor residues in nonameric (9) peptides eluted from two class I MHC molecules Usually hydrophobic

can bind to the same H-2kb Two different nonamers can bind to the same H-2kb Vesicular stomatitis Sendai virus virus (VSV-8) peptide (SEV-9) nucleo- protein

Conformational difference in bound peptides of different lengths

Molecular models based on crystal structure of an influenza virus antigenic peptide and an endogenous peptide bound to a class I MHC molecule influenza virus endogenous

a1 and a2 domains of HLA-B27 and a bound antigenic peptide water molecule

Class II MHC molecules bind peptides and present them to CD4+ T cells – endocytic or exogenous processing pathway

Peptide-binding cleft is open 13 – 18 amino acid residues Peptide-binding cleft is open at both ends in class I molecules 13-18 a.a. residues A central core of 13 a.a. determines the ability of a peptide to bind class II.

Polymorphism of class I and class II molecules - The diversity of the MHC within a species stems from polymorphism, the presence of multiple alleles at a given genetic locus within the species. - The MHC possesses an extraordinarily large number of different alleles at each locus and is one of the most polymorphic genetic complexes known in higher vertebrates. HLA-A 60 alleles H-2K 55 alleles HLA-B 110 alleles H-2D 60 alleles HLA-C 40 alleles - The theoretical diversity possible for the mouse is: 100 (K) x 100 (IAa) x 100 (IAb) x 100 (IEa) x 100 (IEb) x 100 (D) = 1012

Linkage disequilibrium Certain allelic combinations occur more frequently than predicted is referred to as linkage disequilibrium. [Hypothesis]: 1. Sufficient numbers of generations have not elapsed. 2. Certain combinations of alleles are beneficial to the individuals. 3. Crossovers are more frequent in certain DNA sequence regions than in others.

Variability in the amino acid sequence of allelic class I MHC molecules

Location of polymorphic amino acid residues Most of the residues with significant polymorphism are located in the peptide-binding cleft

Class III molecules are not membrane proteins, are not related structurally to class I and class II molecules, and have no role in Ag presentation, although most play some role in immune responses. e.g., C2, C4a, C4b, factor B, 21-hydroxylase enzymes, TNFa, TNFb, heat shock proteins (HSP)

Genetic Map of MHC Genes

Mouse H-2 is on the chromosome 17 Class I Nonclassical Class II Class III Class I Nonclassical

Human HLA is on the chromosome 6 Class II Nonclassical Class II Class III Class I Nonclassical

Cellular Distribution of MHC Molecules

Cellular distribution of MHC class I molecules - In general, the classical MHC class I molecules are expressed on most somatic cells. - The highest level of class I molecules are expressed on lymphocytes: 1 % of the total plasma membrane proteins or 5 x 105 molecules / cell. - Fibroblasts, muscle cells, hepatocytes and neural cells express very low levels of class I molecules. - A few cell types (e.g., neurons and sperm cells at certain stages of differentiation) appear to lack class I MHC molecules altogether.

Cellular distribution of MHC class II molecules - Class II molecules are expressed constitutively only by Ag-presenting cells (APC), e.g., macrophages, dendritic cells, and B cells. - Thymic epithelial cells and some other cell types can be induced to function as APC and then express class II molecules under certain conditions.

Various MHC molecules expressed on APC of a heterozygous H-2k/d mouse

Nonclassical MHC class I and class II molecules - Structurally similar to class I or class II molecules - Less polymorphic - Expressed at lower level - Tissue distribution is more limited - Functions not clear

The End