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Chapter 11 : The Major Histocompatibility Complex

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Abstract:

The (MHC) proteins display peptides on the surface of an antigen-presenting cell (APC). Since T lymphocytes recognize antigen only when the antigen is bound to MHC proteins, the latter play a central role in the acquired immune response. The MHC genes are categorized into three classes on the basis of the structure and function of the proteins they encode. Genes encoding the MHC class I products are located at both ends of the MHC, whereas the genes encoding the MHC class II and class III proteins are located between the two class I regions. In one recent study, this experimental system allowed a tumor-specific human cytotoxic T-lymphocyte clone to be studied in a tumor-bearing mouse that possessed a human MHC transgene. In this study, the antigenic peptide bound to the human MHC proteins and the T-cell antigen receptor (TCR) that recognized the antigen were similar to the peptides and TCR that might work during actual tumor rejection in a human patient. The different types were designated by the particular class I protein followed by a number, given out in nonsequential order. Thus, serologically distinct HLA-A alleles could be classified as HLAA1, -A2, -A3, -A9, etc. However, as more antibody reagents were developed, it became clear that some of the HLA specificities could be further subdivided into a related set.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11

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MHC Class I
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MHC Class II
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Amino Acids
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Major Histocompatibility Complex
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Figures

Image of Figure 11.1
Figure 11.1

General organization of the mouse and human MHC gene clusters. MHC class I genes (orange), which encode proteins that present antigen to CD8+ T cells, are called K, D, and L in mice and A, B, and C in humans. The genes encoding the class II proteins (blue), whose products present antigens to CD4+ T cells, are called IA and IE in mice and DP, DQ, and DR in humans. The class II proteins are the product of two genes (one encoding an MHC α chain and one encoding an MHC β chain). The MHC class III proteins, encoded by genes that lie within the S region, do not function in presentation of antigenic peptides to T lymphocytes. The location of the genes encoding the class III proteins is shown in yellow.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.2
Figure 11.2

()Virtually all cells in the body express MHC class I proteins. Both mice and humans possess three different genes that encode MHC class I proteins. In mice, the MHC class I genes (K, D, and L) are expressed codominantly. Nucleated cells in a mouse express K, D, and L MHC proteins, and nucleated cells in humans express A, B, and C MHC proteins. MHC class II proteins are expressed not by every cell but only by a subset of cells known as APCs. The genes encoding MHC class II proteins IA and IE also are expressed codominantly; therefore, every APC of a mouse expresses both IA and IE proteins. APCs express MHC class I proteins as well as MHC class II proteins.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.3
Figure 11.3

Examples of the system used to name alleles of mouse MHC genes. Allele names, given after the name of the MHC protein, are in italicized superscript. () A hypothetical example. () The names used for an actual mouse haplotype (for the inbred mouse strain C57BL/6). The allele name was taken from the name of the haplotype.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.4
Figure 11.4

()The MHC haplotypes of some commonly used inbred mouse strains. The first five haplotypes, b, d, k, q, and s, have each of the corresponding genes in the MHC designated with the same letter as the overall haplotype. Strain A has the same alleles of the K, IA, and IE genes as strain C3H/HeJ (k), but for the S, D, and L regions, strain A mice have the same alleles as does the BALB/c mouse strain (d). () If two inbred mouse strains (e.g., strain A expressing the H-2 haplotype and strain C57BL/6 expressing the H-2 haplotype) are crossed, the F progeny will be heterozygous at the MHC region. The MHC haplotype of the progeny is referred to as . () The MHC regions of both chromosomes in each of the mice depicted in panel B. The two parental mice are homozygous, whereas the F is heterozygous and bears one MHC haplotype from each parent.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.5
Figure 11.5

() Schematic diagram of a breeding protocol used to generate the MHC-congenic mouse strain A.B. Mice with the haplotype are crossed with mice with the haplotype. After each cross, mice that are homozygous for the MHC haplotype are selected. MHC mice are then repetitively “backcrossed” to the strain to increase the amount of strain A DNA in the congenic strain (selection for the MHC haplotype follows each backcross). () Recombination within the and b haplotypes occurs by two mechanisms. First, entire “sister chromosomes” can be exchanged. Second, recombination can occur within homologous regions of sister chromosomes. This recombination is represented by the F mouse in the dashed box. The chromosomes of the F mouse before recombination are shown above the mouse, and those after recombination are shown below the mouse. Although mouse cells normally have 40 chromosomes, only 10 are shown here for simplicity.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.6
Figure 11.6

The MHC haplotypes of strains SJL ( ) and DBA/2 ( ), MHC-congenic strain SJL.D ( ), and two recombinant congenic strains, SJL.D.(R1) and SJL.D(R2). Strain SJL.D has all of its alleles other than the MHC alleles identical to strain SJL alleles. Strain SJL.D(R1) was generated when a crossover event exchanging the D and L genes on sister chromosomes in heterozygous animals took place, whereas strain SJL.D(R2) is the result of a double crossover event, the first one introducing the entire haplotype into the chromosome of an SJL mouse, and the second event reintroducing the class II genes into the chromosome.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.7
Figure 11.7

Production of MHCtransgenic mice and use in the study of disease. Recombinant DNA encoding different human HLA class II genes (DR3 or DQ6) is inserted into the genome of a starter or founder transgenic mouse lacking the mouse MHC class II genes within the H-2 gene complex on chromosome 17. This results in transgenic mice expressing either human DR3 or DQ6, which will then serve to direct MHC-restricted T-cell selection.Mice expressing the human class II proteins are immunized with the acetylcholine receptor (AchR) to break tolerance and induce antibodies to AchR.Mice carrying human DR3 genes develop disease, whereas mice with DQ6 genes do not. In humans, HLA-DR3 is found more frequently among individuals with MG than is found in the general population, whereas HLA-DQ6 is found less frequently in individuals with MG than in the general population. Increased and decreased frequencies of allelic variants of genes in individuals with a disease such as MG suggest enhanced susceptibility or resistance to the disease, respectively.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.8
Figure 11.8

Interaction of MHC class I or class II with antigenic peptide, the TCR, and the CD4 or CD8 coreceptors. () The MHC proteins on an APC present bound peptide to the TCR that recognizes the complex of the peptide and the MHC. The coreceptors CD4 and CD8 facilitate and stabilize the binding of the APC to the T cell. Despite their differences in structure, the two MHC classes must have sufficient similarities to both to be capable of interacting with peptide- MHC complexes. () Schematic diagrams of MHC class I and class II proteins showing the arrangement of protein domains and the location of the antigen-binding cleft. Domains of MHC class I that are functionally comparable to those in MHC class II share the same colors. MHC class I consists of one transmembrane heavy chain (or α chain) comprising three domains (α, α, and α) and is noncovalently associated with a smaller protein called βm. The peptide-binding cleft of MHC class I is formed by the α and α domains. MHC class II consists of two transmembrane protein chains, α and β. The extracellular region of each protein chain contains two domains (α and α or β and β). The peptide-binding cleft comprises protein sequences derived from both protein chains (the α domain and the β domain).

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.9
Figure 11.9

The molecular structures of MHC class I () and MHC class II (C ) as seen from a side view () or from the top down into the peptide-binding grooves (). The peptide-binding cleft is constructed such that the bottom consists of a β-pleated-sheet lined on both sides by α-helices. In each case the membrane-proximal domains (α and βm for MHC class I and α and β for MHC class II) have a structure similar to typical immunoglobulin domains. In panel D, an antigenic peptide is shown bound in the antigen-binding cleft. Amino acid side chains that participate in contacts between the peptide and the MHC are shown (those of the peptide are in black and those of the MHC are in white). () Two MHC class II proteins. One is shown in black, and the other is shown in gray. The antigenic peptides bound to each MHC class II protein are depicted as light gray ribbons and are located at the top of each class II protein. () Modified with permission from P. J. Bjorkman et al., :506–512, 1987. () Modified with permission from P. Parham, . (Suppl.) 87:11–20, 1990. () Modified with permission from P. H. Shafer et al., . 7:389–398, 1995. () Reprinted with permission from L. J. Stern et al., 368:215–221, 1994.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.10
Figure 11.10

Antigenic peptides that bind to MHC class I interact with the MHC via anchor residues (in bold type) located at or near both ends of the peptide. The figure shows eight different antigenic peptides that can bind to the H-2D MHC class I protein and three different peptides that can bind to the H-2L MHC class I protein. Although the nonanchor residues of the peptides differ considerably, the anchor residues of all the peptides that bind a given MHC protein are identical or in some cases closely related. Note also that the anchor residues that confer binding to H-2D are different from those that confer binding to H-2Ld. Diagram of the interaction of one antigenic peptide with an MHC protein. The physical contact of the anchor residues (residues 2, 3, and 9) with the MHC protein explains the conservation of these residues among peptides that bind the MHC protein. Panel A is modified with permission from V. H. Engelhard, 13–23, 1994.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.11
Figure 11.11

A model of the van der Waals surface of H-2K MHC molecule bound by two different antigenic peptides. The left side shows the vesicular stomatitis virus peptide VSV-8 bound to H-2K; the right side shows the same MHC molecule binding the Sendai virus nucleoprotein peptide SEV-9. Note the conformational differences in the MHC protein surface. Reprinted from M. Matsumura et al., 257:927–934, 1992, with permission.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.12
Figure 11.12

Antigenic peptides that bind MHC class I are anchored to the MHC at both ends and bulge away from the MHC at the middle. The degree to which the peptide bulges from the floor of the binding cleft depends on the length of the peptide, with longer peptides bulging further from the floor of the cleft. (A) Representation of the differences in conformation observed for peptides of 8 amino acids, 9 amino acids, and 10 amino acids bound to an MHC class I protein. (B) The conformations of the bound VSV-8 (8 amino acids) and SEV-9 (9 amino acids) peptides shown in Fig. 11.11 . The bottom of panel B shows the two peptides superimposed to emphasize the “bulge” of the 9-mer bound to MHC. Panel A is modified with permission from P. Parham, 300–301, 1992. Panel B is reprinted with permission from D. Fremont et al., 257:919–927, 1992.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.13
Figure 11.13

Heterozygosity of MHC genes increases the number of different MHC proteins that exist on the surface of a cell. The cell is an APC with the MHC haplotype . The and s MHC alleles are codominantly expressed, meaning that the APC expresses MHC class I of each haplotype on its surface. The variety of MHC class II molecules expressed on the surface is even greater, since the cell expresses not only the parental MHC types (αβ and αβ) but also “hybrid” class II proteins (αβ and αβ).While the IE α chain of one haplotype can pair with the IE β chain of either haplotype (IEαβ or IEαβ), the α chain of IE can pair with IE β chains (not with IA β chains). There is more than one gene encoding the mouse IE β chain, and each of two alleles of the mouse class II IE α chain can produce a protein that pairs up with proteins encoded by either allele of the IE β chain or the IE β2 chain, resulting in eight possible IE proteins on the cell surface.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.14
Figure 11.14

Polymorphism of MHC proteins is concentrated in regions of the MHC protein that interact with antigenic peptide. () Variability is plotted as a function of amino acid position among human MHC class I alleles. Most of the variability among alleles is in the α and α domains; the α domain (which does not bind antigenic peptide) shows little variability. () Amino acids that are highly variable among different MHC alleles (the amino acids in red) are oriented toward the peptide-binding groove. Panel A is reprinted with permission from R. Sodoyer et al., . 879–885, 1984. Panel B is reprinted with permission from P. Parham, . (Suppl.) 11–20, 1990.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.15
Figure 11.15

Detailed genomic maps of the human and mouse MHC gene clusters. Class I genes are in red, class II genes are in blue, and class III genes are in yellow. Genes whose names appear below each diagram are nonclassical MHC genes. The functions of many nonclassical MHC genes are not yet known.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.16
Figure 11.16

The one-way mixed lymphocyte reaction. Three donors of peripheral blood leukocytes are shown; donors 1 and 2 have different MHC class II proteins whereas donors 2 and 3 have the same ones. Leukocytes from donor 2 are irradiated to prevent their proliferating in cell culture and are mixed with leukocytes from donor 1 or donor 3. These are the responder cells. After 3 to 7 days in culture the amount of proliferation of the responder cells is measured. Due to differences in MHC class II between donor 1 and 2, donor 1's lymphocytes recognize the allogeneic class II antigens as foreign and mount a T-cell proliferative response. This can be measured by adding radioactive thymidine to the culture 18 to 24 hours before the end, then harvesting the cells and measuring the amount of radioactivity incorporated into the responding cells' DNA. In contrast, donors 2 and 3 share the same MHC class II haplotype and donor 3 does not recognize donor 2's cells as foreign.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.17
Figure 11.17

Determination of HLA-A type by use of sequence-specific oligonucleotide probes. Arrayed along the strip are lines of oligonucleotides known to represent and differentiate each different HLA-A allele. DNA from test samples is amplified by PCR using primers that are labeled with biotin, thus incorporating the biotin into the test probe. After hybridization, the presence of bound biotin is detected by adding streptavidin coupled to horseradish peroxidase enzyme, followed by a substrate for the enzyme. Those lines with bound probe are then visualized, and computer programs match the pattern to known HLA types. In each lane, there are a reference control and two PCR amplification controls (HLA-A exon 2 and exon 3, which are conserved). Strips 1, 2, 5, 6, and 7 indicate a homozygous genotype, with strips 2, 5, and 6 displaying the pattern for HLA-A0101. Strips 3 and 4 display the HLA-A genotype of a heterozygous individual. The banding pattern serves as a type of fingerprint to genetically identify different HLA alleles. Reprinted from H. A. Erlich et al., 14:347–356, 2001, with permission.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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Image of Figure 11.18
Figure 11.18

Ribbon structure of CD1 molecule illustrating its similarity with classical MHC class I (compare with Fig. 11.9A and B). Like MHC class I, CD1 consists of a transmembrane heavy chain that associates with βm. The α and α domains of CD1 form an antigen-binding cleft that has the same overall shape as an MHC class I antigen-binding cleft. However, the interior of the CD1 cleft, unlike that of the classical MHC class I cleft, is hydrophobic, allowing binding and presentation of lipid antigens, which are also hydrophobic. The positions of alphahelices 1, 2, 2a, and 2b are indicated (H1, H2, H2a, and H2b), as are the positions of betastrands 1, 2, 3, and 4 (S1, S2, S3, and S4) in the α1 and α2 domains. Side view of CD1. Top view of CD1. Reprinted from Z. Zeng et al., 339–345, 1997, with permission.

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
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References

/content/book/10.1128/9781555816148.chap11
1. Alfonso, C.,, and L. Karlsson. 2000. Nonclassical MHC class II molecules. Annu. Rev. Immunol. 18:113142.
2. Hiltbold, E. M.,, and P. A. Roche. 2002. Trafficking of MHC class II molecules in the late secretory pathway. Curr. Opin. Immunol. 14:3035.
3. Maenaka, K.,, and E. Y. Jones. 1999. MHC superfamily structure and the immune system. Curr. Opin. Struct. Biol. 9:745753.
4. Robinson, J. H.,, and A. A. Delvig. 2002. Diversity in MHC class II antigen presentation. Immunology 105:252262.
5. Rouas-Freiss, N.,, R. M. Goncalves,, C. Menier,, J. Dausset,, and E. D. Carosella. 1997. Direct evidence to support the role of HLAG in protecting the fetus from maternal uterine natural killer cytolysis. Proc. Natl. Acad. Sci. USA 94:1152011525.
6. Yeager, M.,, M. Carrington,, and A. L. Hughes. 2000. Class I and class II MHC bind self peptide sets that are strikingly different in their evolutionary characteristics. Immunogenetics 51:815.

Tables

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Table 11.1

Nomenclature of HLA alleles

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
Generic image for table
Table 11.2

Characteristics of the binding of antigenic peptides to MHC class I and class II proteins

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
Generic image for table
Table 11.3

Non-antigen-presenting MHC class I or II proteins and MHC class III proteins

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11
Generic image for table
Table 11.4

Antigen-binding characteristics of human CD1 proteins

Citation: Lyczak J. 2004. The Major Histocompatibility Complex, p 261-282. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch11

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