http://getbooksolutions.com Link full download:https://getbooksolutions.com/download/test-bank-forthe-immune-system-4th-edition-by-parham Test Bank for The Immune System 4th Edition by Parham CHAPTER 5: ANTIGEN RECOGNITION BY T LYMPHOCYTES 5–1 T cells recognize antigen when the antigen forms a complex with membrane-bound MHC molecules on another hostderived cell is internalized by T cells via phagocytosis and subsequently binds to T-cell receptors in the endoplasmic reticulum is presented on the surface of a B cell on membrane-bound immunoglobulins forms a complex with membrane-bound MHC molecules on the T cell bears epitopes derived from proteins, carbohydrates, and lipids 5–2 T-cell receptors structurally resemble the Fc portion of immunoglobulins MHC class I molecules secreted antibodies a single Fab of immunoglobulins CD3 ε chains 5–3 If viewing the three-dimensional structure of a T-cell receptor from the side, with the T-cell membrane at the bottom and the receptor pointing upwards, which of the following is inconsistent with experimental data? The highly variable CDR loops are located across the top surface The membrane-proximal domains consist of Cα and Cβ The portion that makes physical contact with the ligand comprises Vβand Cβ, the domains farthest from the T-cell membrane The transmembrane regions span the plasma membrane of the T cell The cytoplasmic tails of the T-cell receptor α and β chains are very short 5–4 Unlike B cells, T cells not engage in any of the following processes except http://getbooksolutions.com alternative splicing to produce a secreted form of the T-cell receptor alternative splicing to produce different isoforms of the T-cell receptor isotype switching somatic hypermutation somatic recombination 5–5 When comparing the T-cell receptor α-chain locus with the immunoglobulin heavy-chain locus, all of the following are correct except the T-cell receptor α locus differs because it has embedded within its sequence another locus that encodes a different type of T-cell receptor chain both are encoded on chromosome 14 the T-cell receptor α-chain locus does not contain D segments the T-cell receptor α-chain locus contains more V and J regions the T-cell receptor α-chain locus contains more C regions they both contain exons encoding a leader peptide 5–6 Unlike the C regions of immunoglobulin heavy-chain loci, the C regions of the T-cell receptor β-chain loci are functionally similar not contain D segments are more numerous are encoded on a different chromosome from the variable β-chain gene segments of the T-cell receptor not encode a transmembrane region possess non-templated P and N nucleotides 5–7 Which of the following statements regarding Omenn syndrome is incorrect? A bright red, scaly rash is due to a chronic inflammatory condition Affected individuals are susceptible to infections with opportunistic pathogens It is invariably fatal unless the immune system is rendered competent through a bone marrow transplant It is the consequence of complete loss of RAG function There is a deficiency of functional B and T cells http://getbooksolutions.com It is associated with missense mutations of RAG genes 5–8 Identify which features of the RAG genes have similarity to the transposase gene of transposons Explain how the mechanisms for immunoglobulin and T-cell receptor rearrangement may have evolved in humans 5–9 All of the following statements regarding γ:δ T cells are correct except they are more abundant in tissue than in the circulation the δ chain is the counterpart to the β chain in α:β T-cell receptors because it contains V, D, and J segments in the variable region they share some properties with NK cells activation is not always dependent on recognition of a peptide:MHC molecule complex expression on the cell surface is not dependent on the CD3 complex 5–10 Match the term in Column A with its complement in Column B Column A Column B _a T-cell receptor δchain gene positioned in the T-cell receptor α-chain locus between Vα and Jα gene segments _b CD3 complex made up of γ, δ and ε components http://getbooksolutions.com _c T-cell receptor βchain gene located on chromosome _d CD4 counterpart to the Tcell receptor α-chain gene _e T-cell receptor γchain gene four extracellular domains 5–11 During T-cell receptor _-gene rearrangement, two D segments may be used in the final rearranged gene sequence, thereby increasing overall variability of this chain α β γ δ ε 5–12 The degradation of pathogen proteins into smaller fragments called peptides is a process commonly referred to as endocytosis promiscuous processing antigen processing antigen presentation peptide loading 5–13 All of the following are primarily associated with CD4 T-cell function except improve phagocytic mechanisms of tissue macrophages assist B cells in the production of high-affinity antibodies http://getbooksolutions.com kill virus-infected cells facilitate responses of other immune-system cells during infection assist macrophages in sustaining adaptive immune responses through their secretion of cytokines and chemokines 5–14 The primary reason for transplant rejections is due to differences in _ between donor and recipient CD3 MHC molecules T-cell receptor α chains γ:δ T cells β2-microblobulin 5–15 Explain the importance of promiscuous binding specificity exhibited by MHC class I and class II molecules 5–16 When describing the various components of the vesicular system, which of the following is not included? nucleus Golgi apparatus endoplasmic reticulum exocytic vesicles lysosomes 5–17 Which of the following is not a characteristic of immunoproteasomes? They make up about 1% of cellular protein They consist of four rings of seven polypeptide subunits that exist in alternative forms They are produced in response to IFN-γ produced during innate immune responses They produce a higher proportion of peptides containing acidic amino acids at the carboxy terminus compared with constitutive proteasomes http://getbooksolutions.com They contain 20S proteasome-activation complexes on the caps 5–18 Identify which of the following statements is true regarding the transporter associated with antigen processing (TAP) TAP is a homodimer composed of two identical subunits TAP transports proteasome-derived peptides from the cytosol directly to the lumen of the Golgi apparatus TAP is an ATP-dependent, membrane-bound transporter Peptides transported by TAP bind preferentially to MHC class II molecules TAP deficiency causes a type of bare lymphocytes syndrome resulting in severely depleted levels of MHC class II molecules on the surface of antigenpresenting cells 5–19 All of the following are included in the peptide-loading complex except tapasin calnexin calreticulin ERp57 β2-microglobulin 5–20 Which of the following best describes the function of tapasin? Tapasin is an antagonist of HLA-DM and causes more significant increases in MHC class I than MHC class II on the cell surface Tapasin is a lectin that binds to sugar residues on MHC class I molecules, Tcell receptors, and immunoglobulins and retains them in the ER until their subunits have adopted the correct conformation Tapasin is a thiol-reductase that protects the disulfide bonds of MHC class I molecules Tapasin participates in peptide editing by trimming the amino terminus of peptides to ensure that the fit between peptide and MHC class II molecules is appropriate Tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules http://getbooksolutions.com 5–21 The mechanisms contributing to peptide editing include which of the following? (Select all that apply.) removal of amino acids from the amino-terminal end by endoplasmic reticulum aminopeptidase (ERAP) cathepsin S-mediated cleavage of invariant chain the participation of tapasin in finding a ‘good fit’ for class I heterodimers recycling an MHC class I heterodimer if the peptide falls out of its peptidebinding groove upregulation of HLA-DM by interferon-γ 5–22 Match the term in Column A with its description or function in Column B Column A Column B _a cathepsin S a chaperone that directs empty MHC class I molecules to the inside of the cell _b HLA-DM activated by acidification in phagolysosomes _c endoplasmic reticulum aminopeptidase (ERAP) a thiol-reductase in the peptide-loading complex _d receptor-mediated endocytosis removes class IIassociated invariant-chain peptide (CLIP) _e ERp57 internalization of http://getbooksolutions.com immunoglobulin:antigen complexes by B cells _f HLA-G expressed only by extravillous trophoblasts _g HLA-F trims peptides to fit MHC class I molecules 5–23 Explain how mycobacteria avoid immune recognition by T cells during infection 5–24 Identify the three functions of the invariant chain 5–25 Explain specifically how interferon-γ produced during an infection enhances (A) antigen processing in the MHC class I pathway, and (B) antigen presentation in the MHC class II pathway 5–26 Discuss how T-cell receptors differ from immunoglobulins in the way that they recognize antigen Use the following terms in your answer: peptides, antigenpresenting cells, MHC molecules, and antigen-binding sites 5–27 Pathogens that infect the human body replicate either inside cells (such as viruses) or extracellularly, in the blood or in the extracellular spaces in tissues Identify (i) the class of T cells that are stimulated by intracellular pathogens, (ii) their co-receptor, (iii) the MHC molecule used for recognition of antigen and (iv) the T-cell effector function http://getbooksolutions.com Repeat this for the classes of T cells that are stimulated by extracellular pathogens For the purposes of this question, count those pathogens (such as mycobacteria) that can survive and live inside intracellular vesicles after being taken up by macrophages as extracellular pathogens 5–28 In contrast to immunoglobulins, α:β T-cell receptors recognize epitopes present on _ antigens: carbohydrate lipid protein carbohydrate and lipid carbohydrate, lipid, and protein 5–29 Indicate whether each of the following statements regarding T cells is true (T) or false (F) T cells and B cells recognize the same types of antigen T cells and B cells require MHC molecules for the recognition of peptide antigens T cells require an accessory cell called an antigen-presenting cell, which bears MHC molecules on its surface T-cell receptor and immunoglobulin genes are encoded on the MHC The T-cell receptor has structural similarity to an immunoglobulin Fab fragment 5–30 Which of the following characteristics is common to both T-cell receptors and immunoglobulins? Somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites Somatic hypermutation changes the affinity of antigen-binding sites and contributes to further diversification Class switching enables a change in effector function The antigen receptor is composed of two identical heavy chains and two identical light chains http://getbooksolutions.com Carbohydrate, lipid, and protein antigens are recognized and stimulate a response 5–31 The antigen-recognition site of T-cell receptors is formed by the association of which of the following domains? Vα and Cα Vβ and Cβ Cα and Cβ Vα and Cβ Vα and Vβ 5–32 The most variable parts of the T-cell receptor are Vα and Cα Vβ and Cβ Cα and Cβ Vα and Cβ Vα and Vβ 5–33 How many complementarity-determining regions contribute to the antigenbinding site in an intact T-cell receptor? 12 5–34 IgG possesses _ binding sites for antigen, and the T-cell receptor possesses _ binding sites for antigen: 1; 2; 1; http://getbooksolutions.com 5–12 c 5–13 c 5–14 b 5–15 Each MHC molecule can bind to a very large number of peptides made up of different sequences of amino acids The consequence of this promiscuity is that humans need only encode a relatively small number of MHC molecules in their genome if they are to bind to the huge number of pathogen-derived peptides encountered during a lifetime of infections Because MHC molecules are coexpressed on the cell surface, this also ensures that an appropriate density of MHC molecules populates the cell surface to ensure efficient T-cell engagement and subsequent activation 5–16 a 5–17 d 5–18 c 5–19 b 5–20 e 5–21 a, c, d http://getbooksolutions.com 5–22 a—2; b—4; c—7; d—5; e—3; f—6; g—1 5–23 Both the MHC class I and MHC class II pathways are subverted by mycobacteria during intracellular growth and replication Although mycobacteria are obligate intracellular pathogens their proteins not enter the cytosol, so proteasomes are unable to generate mycobacteria-derived peptides for the MHC class I pathway Mycobacteria are also resistant to degradation by lysosomal enzymes because they inhibit phagolysosome formation This interferes with the MHC class II pathway 5–24 Invariant chain protects the peptide-binding groove of MHC class II molecules from binding to endoplasmic reticulum-derived peptides Binding of invariant chain to MHC class II molecules stabilizes their conformation so that they are eventually able to bind peptides Invariant chain facilitates the transport of MHC class II molecules from the ER to the MIIC cellular compartment, where they can bind peptides 5–25 Interferon-γ causes a shift from the production of constitutive proteasomes to that of immunoproteasomes This is accomplished through increased expression of alternative subunits (LMP2 and LMP7) that are present in the immunoproteasome These proteasomes exhibit modified protease activities favoring the production of peptides (antigen processing) that can bind to MHC class I molecules Specifically, cleavage after hydrophobic residues is enhanced and cleavage after acidic residues is decreased Interferon-γ increases the expression of HLA-DM but not HLA-DO This causes a shift in the balance of these two molecules, resulting in an overall decrease in the antagonist activity of HLA-DO If HLA-DM is more abundant, it has the ability to catalyze the release of CLIP from MHC class II molecules and facilitate the replacement of CLIP with other peptides for presentation to CD4 T cells (antigen presentation) Another way in which interferon-γ increases antigen presentation in the MHC class II pathway is by increasing the expression levels of MHC class II molecules on both professional and nonprofessional antigen-presenting cells http://getbooksolutions.com 5–26 First, T-cell receptors can bind to only one type of antigen, namely protein fragments called peptides Immunoglobulins can bind to peptides, intact proteins, carbohydrates, and lipids Second, unlike immunoglobulins, T-cell receptors cannot bind to a free antigen directly, but instead require accessory antigen-presenting cells that present the peptide antigens in association with cell-surface glycoproteins called MHC class I and class II molecules Third, T-cell receptors possess a single antigen-binding site; immunoglobulins have at least two binding sites for antigen, and more in the case of secreted dimeric IgA (four sites) and secreted pentameric IgM (ten sites) 5–27 (i) Pathogens that are propagating freely within cells (for example viruses) are eradicated by the actions of cytotoxic T cells (ii) Cytotoxic T cells express a glycoprotein called CD8, a T-cell co-receptor that interacts with (iii) MHC class I on antigen-presenting cells (iv) Once activated, cytotoxic T cells kill cells infected with the pathogen, which are displaying pathogen peptides on MHC class I molecules, and thereby inhibit further replication of the pathogen and infection of neighboring cells (i) Pathogens that reproduce in extracellular spaces, for example encapsulated bacteria such as Streptococcus pneumoniae, are eradicated after the activation of other cell types by helper T cells, namely the classes TH1 and TH2 (ii) TH1 and TH2 cells express a glycoprotein called CD4, a T-cell coreceptor that interacts with (iii) MHC class II molecules on antigen-presenting cells (iv) TH1 cells activate macrophages that are displaying pathogen peptides (derived from phagocytosed pathogen) on MHC class II molecules on their surface This stimulates increased phagocytosis by the macrophage and destruction of pathogens inside phagolysosomes Activated macrophages also secrete inflammatory mediators that have an important part in eradicating the infection by helping to induce inflammation which recruits phagocytic cells and effector lymphocytes to the site of infection TH1 cells also induce switching of B cells to certain antibody isotypes TH2 cells activate B cells displaying antigen-derived peptides on MHC class II molecules, resulting in the differentiation of the B cells into plasma cells and the production of antibodies that remove the extracellular pathogen or its toxins as a result of neutralization, opsonization, and complement activation http://getbooksolutions.com 5–28 c 5–29 a—F; b—F; c—T; d—F; e—T 5–30 a 5–31 e 5–32 e 5–33 d 5–34 b 5–35 c 5–36 e 5–37 b 5–38 Professional antigen-presenting cells express several different types of MHC molecule on the cell surface, and each type has the potential to bind to different peptides In addition, MHC molecules are highly polymorphic, so that most individuals are heterozygous and encode different allelic forms at each gene locus The variety of peptides that can bind to these MHC molecules is therefore increased http://getbooksolutions.com 5–39 b 5–40 a 5–41 d 5–42 a 5–43 c 5–44 a 5–45 e 5–46 a 5–47 e 5–48 d 5–49 e 5–50 a http://getbooksolutions.com 5–51 c 5–52 a, d 5–53 d 5–54 b, d 5–55 e 5–56 c 5–57 b 5–58 b 5–59 a, d 5–60 e 5–61 b http://getbooksolutions.com 5–62 MHC class I molecules not only have the role of presenting antigen to T cells, but they also possess additional functions in the body not associated with MHC class II molecules For example, they participate in iron homeostasis, IgG uptake in the gastrointestinal tract, and the regulation of NK-cell function in innate immunity In addition, MHC class I and class I-like genes are not confined to chromosome 6, in contrast with MHC class II genes Finally, vertebrates exist (such as Atlantic cod) that have only MHC class I genes in their genome, and lack MHC class II genes 5–63 a—3; b—1; c—5; d—2; e—4 5–64 d 5–65 Similarities (1) The T-cell receptor has a similar overall structure to the membrane-bound Fab fragment of immunoglobulin, containing an antigenbinding site, two variable domains, and two constant domains (2) T-cell receptors and immunoglobulins are both generated through somatic recombination of sets of gene segments (3) The variable region of the T-cell receptor contains three complementarity-determining regions (CDRs) encoded by the Vαdomain and three CDRs encoded by the Vβ domain, analogous to the CDRs encoded by the VH and VL domains (4) There is huge diversity in the T-cell receptor repertoire and it is generated in the same way as that in the B-cell repertoire (by combination of different gene segments, junctional diversity due to P- and N-nucleotides, and combination of two different chains) (5) T-cell receptors are not expressed at the cell surface by themselves but require association with the CD3 γ, δ, ε, and ζ chains for stabilization and signal transduction, analogous to the Igα and Igβ chains required for immunoglobulin cell-surface expression and signal transduction Differences (1) A T-cell receptor has one antigen-binding site; an immunoglobulin has at least two (2) T-cell receptors are never secreted (3) T-cell receptors are generated in the thymus, not the bone marrow (4) The constant region of the T-cell receptor has no effector function and it does not switch isotype (5) T-cell receptors not undergo somatic hypermutation http://getbooksolutions.com 5–66 The organization of the TCRα locus resembles that of an immunoglobulin light-chain locus, in that both contain V and J gene segments and no D gene segments The TCRα locus on chromosome 14 contains about 80 V gene segments, 61 J gene segments, and C gene The immunoglobulin light-chain loci, λ and κ, are encoded on chromosomes 22 and 2, respectively The λ locus contains about 30 V gene segments and J gene segments, each paired with a C gene The κ locus contains about 35 V gene segments, J segments, and C gene segment The arrangement of the κ locus more closely resembles that of the TCRα locus except that there are more J segments in the T-cell receptor locus The organization of the TCRβ locus resembles that of the immunoglobulin heavychain locus; both contain V, D, and J gene segments The TCRβ locus contains about 52 V gene segments, D gene segments, 13 J gene segments, and C genes, encoded on chromosome Each C gene is associated with a set of D and J gene segments The immunoglobulin heavy-chain locus on chromosome 14 contains about 40 V segments, 23 D segments, and J segments, followed by C genes, each specifying a different immunoglobulin isotype The heavy-chain C genes determine the effector function of the antibody 5–67 T-cell receptors are not made in a secreted form, and their constant regions not contribute to T-cell effector function Other molecules secreted by T cells are used for effector functions There is therefore no need for isotype switching in T cells, and the T-cell receptor loci not contain numerous alternative C genes 5–68 a 5–69 a, c, d 5–70 a 5–71 (i) The complete MHC class I molecule is a heterodimer made up of one α chain and a smaller chain called β-microglobulin The α chain consists of http://getbooksolutions.com three extracellular domains α1, α2, and α3—a transmembrane region and a cytoplasmic tail β2-Microglobulin is a single-domain protein noncovalently associated with the extracellular portion of the α chain, providing support and stability (ii) The polymorphic class I molecules in humans are called HLA-A, HLA-B, and HLA-C The α chain is encoded in the MHC region by an MHC class I gene The gene for β2-microglobulin is elsewhere in the genome (iii) The antigen-binding site is formed by the α1 and α2 domains, the ones farthest from the membrane, which create a peptide-binding groove The region of the MHC molecule that binds to the T-cell receptor encompasses the α helices of the α1 and α2 domains that make up the outer surfaces of the peptide-binding groove The α3 domain binds to the T-cell co-receptor CD8 (iv) The most polymorphic parts of the α chain are the regions of the α1 and α2 domains that bind antigen and the T-cell receptor β2-Microglobulin is invariant; that is, it is the same in all individuals (i) MHC class II molecules are heterodimers made up of an α chain and a β chain The α chain consists of α1 and α2 extracellular domains, a transmembrane region, and a cytoplasmic tail The β chain contains β1 and β2 extracellular domains, a transmembrane region, and a cytoplasmic tail (ii) In humans there are three polymorphic MHC class II molecules called HLADP, HLA-DQ, and HLA-DR Both chains of an MHC class II molecule are encoded by genes in the MHC region (iii) Antigen binds in the peptidebinding groove formed by the α1 and β1domains The α helices of the α1 and β1 domains interact with the T-cell receptor The β2 domain binds to the T-cell co-receptor CD4 (iv) With the exception of HLA-DRα, which is dimorphic, both the α and β chains of MHC class II molecules are highly polymorphic Polymorphism is concentrated around the regions that bind antigen and the T-cell receptor in the α1 and β1 domains 5–72 Antigen processing is the intracellular breakdown of pathogen-derived proteins into peptide fragments that are of the appropriate size and specificity required to bind to MHC molecules Antigen presentation is the assembly of peptides with MHC molecules and the display of these complexes on the surface of antigen-presenting cells Antigen processing and presentation must occur for T cells to be activated because (1) T-cell receptors cannot bind to intact protein, only to peptides, and (2) T-cell receptors not bind antigen directly, but rather must recognize antigen bound to MHC molecules on the surface of antigenpresenting cells http://getbooksolutions.com 5–73 Proteins derived from pathogens located in the cytosol are broken down into small peptide fragments in proteasomes The peptides are transported into the lumen of the endoplasmic reticulum (ER) using the transporter associated with antigen processing (TAP), which is a heterodimer of TAP-1 and TAP-2 proteins anchored in the ER membrane Meanwhile, MHC class I molecules are assembling and folding in the ER with the assistance of other proteins Initially, the MHC class I α chain binds calnexin through an asparagine-linked oligosaccharide on the α1 domain After folding and forming its disulfide bonds, the α chain binds to β2-microglobulin, forming the MHC class I heterodimer At this stage, calnexin is released and the heterodimer joins the peptide-loading complex composed of tapasin, calreticulin, and ERp57, which position the heterodimer near TAP, stabilize the peptide-loading complex, and render the heterodimer in an open conformation until a high-affinity peptide binds to the heterodimer through a process known as peptide editing The heterodimer consequently changes its conformation, is released from the peptide-loading complex, and leaves the ER as a vesicle Arrival at the Golgi apparatus induces final glycosylation, and finally the peptide:MHC class I heterodimer complex is transported in vesicles to the plasma membrane, where it presents peptide to CD8 T cells (i) If an MHC class I α chain is unable to bind β2-microglobulin, it will be retained in the ER and will not be transported to the cell surface It will remain bound to calnexin and will not fold into the conformation needed to bind to peptide Thus, antigens will not be presented using that particular MHC class I molecule (ii) If TAP-1 or TAP-2 proteins are mutated and not expressed, peptides will not be transported into the lumen of the ER Without peptide, an MHC class I molecule cannot complete its assembly and will not leave the ER A rare immunodeficiency disease called bare lymphocyte syndrome (MHC class I immunodeficiency) is characterized by a defective TAP protein, causing less than 1% of MHC class I molecules to be expressed on the cell surface in comparison with normal Thus, T-cell responses to all pathogen antigens that would normally be recognized on MHC class I molecules will be impaired 5–74 a http://getbooksolutions.com 5–75 Extracellular pathogens are taken up by endocytosis or phagocytosis and degraded by enzymes into smaller peptide fragments inside acidified intracellular vesicles called phagolysosomes MHC class II molecules delivered into the ER and being transported to the cell surface intersect with the phagolysosomes, where these peptides are encountered and loaded into the antigen-binding groove To prevent MHC class II molecules from binding to peptides prematurely, invariant chain (Ii) binds to the MHC class II antigen-binding site in the ER Ii is also involved in transporting MHC class II molecules to the phagolysosomes via the Golgi as part of the interconnected vesicle system Ii is removed from MHC class II molecules once the phagolysosome is reached Removal is achieved in two steps: (1) proteolysis cleaves Ii into smaller fragments, leaving a small peptide called CLIP (class IIassociated invariant chain peptide) in the antigen-binding groove of the MHC class II molecule; and (2) CLIP is then released by HLA-DM catalysis Once CLIP is removed, HLA-DM remains associated with the MHC class II molecule, enabling the now empty peptide-binding groove to sample other peptides until one binds tightly enough to cause a conformational change that releases HLA-DM Finally, the peptide:MHC class II complex is transported to the plasma membrane (i) Defects in the invariant chain would impair normal MHC class II function because invariant chain not only protects the peptide-binding groove from binding prematurely to peptides present in the ER but is also required for transport of MHC class II molecules to the phagolysosome (ii) If HLA-DM were not expressed, most MHC class II molecules on the cell surface would be occupied by CLIP rather than endocytosed material This would compromise the presentation of extracellular antigens at the threshold levels required for T-cell activation 5–76 Multigene family refers to the presence of multiple genes for MHC class I and MHC class II molecules in the genome, encoding a set of structurally similar proteins with similar functions MHC polymorphism is the presence of multiple alleles (in some cases several hundreds) for most of the MHC class I and class II genes in the human population T cells recognize peptide antigens in the form of peptide:MHC complexes, which they bind using their T-cell receptors To bind specifically, the T-cell receptor must fit both the peptide and the part of the MHC molecule http://getbooksolutions.com surrounding it in the peptide-binding groove (i) Because each individual expresses a number of different MHC molecules from the MHC class I and class II multigene families, the T-cell receptor repertoire is not restricted to recognizing peptides that bind to just one MHC molecule (and thus all must have the same peptide-binding motif) Instead, the T-cell receptor repertoire can recognize peptides with different peptide-binding motifs during an immune response, increasing the likelihood of antigen recognition and, hence, T-cell activation (ii) The polymorphism in MHC molecules is localized to the regions affecting T-cell receptor and peptide binding Thus, a T-cell receptor that recognizes a given peptide bound to variant ‘a’ of a particular MHC molecule is likely not to recognize the same peptide bound to variant ‘b’ of the same MHC molecule Polymorphism also means that the MHC molecules of one person will bind a different set of peptides from those in another person Taken together, these outcomes mean that because of MHC polymorphism, each individual recognizes a somewhat different range of peptide antigens using a different repertoire of T-cell receptors 5–77 MHC polymorphisms are non-randomly localized, predominantly to the region of the molecule that makes contact with peptide and T-cell receptors Random DNA mutations, in contrast, would be scattered through the gene, giving rise to amino acid changes throughout MHC molecules and not just in those areas important for peptide binding and presentation 5–78 d 5–79 c 5–80 c 5–81 b 5–82 a http://getbooksolutions.com 5–83 b 5–84 a—3; b—1, 2; c—5; d—4; e—1 5–85 e 5–86 m and p denote maternal and paternal allotypes, respectively The answer is The possible combinations are as follows: (1) DRA-m:DRB1-m; (2) DRA-m:DRB1-p; (3) DRA-m:DRB4-p; (4) DRA-p:DRB1-m; (5) DRA-p:DRB1-p; and (6) DRA-p:DRB4-p The answer is The possible combinations are as follows: (1) DRA-m:DRB1-m; (2) DRA-m:DRB3-m; (3) DRA-m:DRB1-p; (4) DRA-m:DRB4-p; (5) DRA-p:DRB1-m; (6) DRA-p:DRB3-m; (7) DRA-p:DRB1-p; (8) DRA-p:DRB4-p 5–87 e 5–88 a 5–89 There are three MHC class I isotypes in humans (HLA-A, HLA-B, and HLA-C) and they are expressed from both chromosomes Assuming that each gene is heterozygous, the maximum number of different MHC class I α chains that could be expressed is Because β-microglobulin is invariant, this means that six different MHC class I molecules could be produced For MHC class II molecules, assuming complete heterozygosity and the presence of two functional DRB genes (DRB1 and DRB3, 4, or 5) on both chromosomes, the http://getbooksolutions.com maximum number of MHC class II molecules that could be expressed is 16 (Figure A5–89) Therefore, the total number of different MHC class I and MHC class II molecules that can be expressed is 22 Figure A5–89 The number of HLA molecules that can be expressed in a single individual m, maternal chromosome; p, paternal chromosome MHC molecules have promiscuous binding specificity, which means that one MHC molecule is able to bind a wide range of peptides with different sequences For all MHC molecules, only a few of the amino acids in the antigen peptide are critical for binding to amino acids in the peptide-binding groove The critical amino acids in the peptide are called anchor residues; they are the same or similar in all peptides that bind to a given MHC molecule The other amino acid residues in the peptides can be different The pattern of anchor residues that binds to a given MHC molecule is called the peptide-binding motif Hence, a very large number of discrete peptides can bind to each MHC isoform, the only constraint being the possession of the correct anchor residues at the appropriate positions in the peptide MHC class I molecules also bind peptides that are typically nine amino acids long, whereas MHC class II molecules bind longer peptides with a range of lengths 5–90 Interallelic conversion is a recombination between homologous alleles of the same gene Gene conversion is a recombination between non-homologous alleles of different genes An example of interallelic conversion would involve recombination between HLA B*5101 and HLA B*3501 An example of gene conversion would involve recombination between HLA B*1501 and HLA Cw*0102 http://getbooksolutions.com 5–91 Balancing selection maintains a variety of MHC isoforms in a population, whereas directional selection replaces older isoforms with newer variants 5–92 Alloantibodies are antibodies specific for variant antigens encoded at polymorphic genes within a species (for example blood group antigens and MHC class I and class II molecules) They arise naturally during pregnancy when the mother’s immune system encounters fetal cells expressing variant antigens derived from the father but not expressed by the mother If present, alloantibodies with specificity for transplanted organs will mediate graft rejection ... MHC region by an MHC class I gene The gene for β2-microglobulin is elsewhere in the genome (iii) The antigen-binding site is formed by the α1 and α2 domains, the ones farthest from the membrane,... encoded by genes in the MHC region (iii) Antigen binds in the peptidebinding groove formed by the α1 and β1domains The α helices of the α1 and β1 domains interact with the T-cell receptor The β2... chains form the periphery of the binding site making contact with the α helices of the MHC molecule The most variable part of the T-cell receptor is composed of the CD3 loops of both the α and