4Th_Ed Test Bank The Immune System – Parham
THE IMMUNE SYSTEM, FOURTH EDITION
CHAPTER 5: ANTIGEN RECOGNITION BY T LYMPHOCYTES
© 2015 Garland Science
5–1 T cells recognize antigen when the antigen
- forms a complex with membrane-bound MHC molecules on another host-derived 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 Vβ and 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 do not engage in any of the following processes except
- 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
- do 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
- do 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.
- It is associated with missense mutations of RAG genes.
- 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 δ-chain gene||1. positioned in the T-cell receptor α-chain locus between Vα and Jα gene segments
|___b. CD3 complex||2. made up of γ, δ and ε components
|___c. T-cell receptor β-chain gene||3. located on chromosome 7|
|___d. CD4||4. counterpart to the T-cell receptor α-chain gene|
|___e. T-cell receptor γ-chain gene||5. 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.
5–12 The degradation of pathogen proteins into smaller fragments called peptides is a process commonly referred to as
- 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
- 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.
- MHC molecules
- T-cell receptor α chains
- γ:δ T cells
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?
- Golgi apparatus
- endoplasmic reticulum
- exocytic vesicles
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.
- 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 antigen-presenting cells.
5–19 All of the following are included in the peptide-loading complex except
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, T-cell 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.
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 peptide-binding 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
|1. a chaperone that directs empty MHC class I molecules to the inside of the cell|
|2. activated by acidification in phagolysosomes|
|___c. endoplasmic reticulum aminopeptidase (ERAP)||3. a thiol-reductase in the peptide-loading complex|
|___d. receptor-mediated endocytosis||4. removes class II-associated invariant-chain peptide (CLIP)|
|___e. ERp57||5. internalization of immunoglobulin:antigen complexes by B cells
|___f. HLA-G||6. expressed only by extravillous trophoblasts|
|___g. HLA-F||7. 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, antigen-presenting 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.
- 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 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.
- 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 antigen-binding site in an intact T-cell receptor?
5–34 IgG possesses _______ binding sites for antigen, and the T-cell receptor possesses _______ binding sites for antigen:
- 1; 1
- 2; 1
- 1; 2
- 2; 2
- 2; 4.
5–35 In terms of V, D, and J segment arrangement, the T-cell receptor α-chain locus resembles the immunoglobulin _______ locus, whereas the T-cell receptor β-chain locus resembles the immunoglobulin _______ locus:
- λ light chain; κ light chain
- heavy chain; λ light chain
- κ light chain; heavy chain
- λ light chain; heavy chain
- κ light chain; λ light chain.
5–36 In B cells, transport of immunoglobulin to the membrane is dependent on association with two invariant proteins, Igα and Igβ. Which of the following invariant proteins provide this function for the T-cell receptor in T cells?
- All of the above.
5–37 Owing to the location of the δ-chain locus of the T-cell receptor on chromosome 14, if the _______-chain locus rearranges by somatic recombination, then the δ-chain locus is _______:
- α; also rearranged
- α; deleted
- α; transcribed
- β; deleted
- γ; also rearranged.
5–38 Explain how professional antigen-presenting cells optimize antigen presentation to T cells despite the relatively limited capacity of any particular MHC molecule to bind different pathogen-derived peptides.
5–39 Which of the following is not a characteristic of native antigen recognized by T cells?
- peptides ranging between 8 and 25 amino acids in length
- not requiring degradation for recognition
- amino acid sequences not found in host proteins
- primary, and not secondary, structure of protein
- binding to major histocompatibility complex molecules on the surface of antigen-presenting cells.
5–40 Which of the following statements regarding CD8 T cells is incorrect?
- When activated, CD8 T cells in turn activate B cells.
- CD8 is also known as the CD8 T-cell co-receptor.
- CD8 binds to MHC molecules at a site distinct from that bound by the T-cell receptor.
- CD8 T cells kill pathogen-infected cells by inducing apoptosis.
- CD8 T cells are MHC class I-restricted.
5–41 Antigen processing involves the breakdown of protein antigens and the subsequent association of peptide fragments on the surface of antigen-presenting cells with
- T-cell receptors
- complement proteins
- MHC class I or class II molecules
5–42 Which of the following statements regarding T-cell receptor recognition of antigen is correct?
- α:β T-cell receptors recognize antigen only as a peptide bound to an MHC molecule.
- αβ T-cell receptors recognize antigens in their native form.
- α:β T-cell receptors, like B-cell immunoglobulins, can recognize carbohydrate, lipid, and protein antigens.
- Antigen processing occurs in extracellular spaces.
- Like α:β T cells, γ:δ T cells are also restricted to the recognition of antigens presented by MHC molecules.
5–43 Which of the following describes a ligand for an α:β T-cell receptor?
- carbohydrate:MHC complex
- lipid:MHC complex
- peptide:MHC complex
- all of the above
- none of the above.
5–44 MHC class II molecules are made up of two chains called _______, whose function is to bind peptides and present them to _______ T cells:
- alpha (α) and beta (β); CD4
- alpha (α) and beta2-microglobulin (β2m); CD4
- alpha (α) and beta (β); CD8
- alpha (α) and beta2-microglobulin β2m); CD8
- alpha (α) and beta (β); γ:δ T cells.
5–45 The complementarity-determining region (CDR) 1 and CDR2 loops of the T-cell receptor contact the _______:
- side chains of amino acids in the middle of the peptide
- co-receptors CD4 or CD8
- membrane-proximal domains of the MHC molecule
- constant regions of antibody molecules
- α helices of the MHC molecule.
5–46 The CDR3 loops of the T-cell receptor contact the _______:
- side chains of amino acids in the middle of the peptide
- co-receptors CD4 or CD8
- membrane-proximal domains of the MHC molecule
- constant regions of antibody molecules
- α helices of the MHC molecule.
5–47 The peptide-binding groove of MHC class I molecules is composed of the following extracellular domains:
5–48 To which domain of MHC class II does CD4 bind?
5–49 To which domain of MHC class I does CD8 bind?
5–50 MHC molecules have promiscuous binding specificity. This means that
- a particular MHC molecule has the potential to bind to different peptides
- when MHC molecules bind to peptides, they are degraded
- peptides bind with low affinity to MHC molecules
- none of the above describes promiscuous binding specificity.
5–51 T-cell receptors interact not only with peptide anchored in the peptide-binding groove of MHC molecules, but also with
- anchor residues
- peptide-binding motif
- variable amino acid residues on α helices of the MHC molecule
- invariant chain.
5–52 Cross-priming of the immune response occurs when _____. (Select all that apply.)
- viral antigens are presented by MHC class I molecules on the surface of a cell that is not actually infected by that particular virus
- cytosol-derived peptides enter the endoplasmic reticulum and bind to MHC class II molecules
- phagolysosome-derived peptides bind to MHC class II molecules
- peptides of nuclear or cytosolic proteins are presented by MHC class II molecules.
5–53 In reference to the interaction between T-cell receptors and their corresponding ligands, which of the following statements is correct?
- The organization of the T-cell receptor antigen-binding site is distinct from the antigen-binding site of immunoglobulins.
- The orientation between T-cell receptors and MHC class I molecules is different from that of MHC class II molecules.
- The CDR3 loops of the T-cell receptor α and β 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 β chains.
- All of the above statements are correct.
5–54 The diversity of MHC class I and II genes is due to _____. (Select all that apply.)
- gene rearrangements similar to those observed in T-cell receptor genes
- the existence of many similar genes encoding MHC molecules in the genome
- somatic hypermutation
- extensive polymorphism at many of the alleles
- isotype switching.
5–55 The combination of all HLA class I and class II allotypes that an individual expresses is referred to as their
- HLA type.
5–56 All of the following are oligomorphic except
- HLA-G α chain
- HLA-DO β chain
- HLA-DQ β chain
- HLA-A α chain
- HLA-DR α chain.
5–57 All of the following are highly polymorphic except
- HLA-A α chain
- HLA-DO α chain
- HLA-B α chain
- HLA-DR β chain
- HLA-C α chain.
5–58 Of the following HLA α-chain loci, which one exhibits the highest degree of polymorphism?
5–59 Which of the following are not encoded on chromosome 6 in the HLA complex? (Select all that apply.)
- HLA-G α chain
- invariant chain
- HLA-DR α chain.
5–60 The _____ refers to the complete set of HLA alleles that a person possesses on a particular chromosome 6.
5–61 Peptides that bind to a particular MHC isoform usually have either the same or chemically similar amino acids at two to three key positions that hold the peptide tightly in the peptide-binding groove of the MHC molecule. These amino acids are called _____ and the combination of these key residues is known as its _____.
- alleles; allotypes
- anchor residues; peptide-binding motif
- allotype; haplotypes
- invariant chains; haplotypes
- restriction residues; MHC allotype.
5–62 Provide an explanation of why it is believed that MHC class I genes are the evolutionary ancestors of MHC class II genes.
5–63 Match the term in Column A with its description in Column B.
|Column A||Column B|
|___a. MHC restriction||1. mechanism enabling extracellular antigens to bind to MHC class I molecules|
|___b. cross-presentation||2. evolutionary maintenance of divergent MHC molecule phenotypes|
|___c. heterozygote advantage||3. recognition of peptide antigen by a given T-cell receptor when bound to a particular MHC allotype|
|___d. balancing selection||4. mechanism used to increase polymorphisms of HLA class I and class II alleles involving homologous recombination between different alleles of the same gene|
|___e. interallelic conversion||5. presentation of a wider range of peptides when MHC isotypes inherited from each parent are different|
5–64 Directional selection is best described as
- all polymorphic alleles preserved in a population
- T-cell receptor interaction with peptide:MHC complexes directed to a planar interface
- a mechanism in T cells that is analogous to affinity maturation of immunoglobulins
- selected alleles increase in frequency in a population
- selection of most appropriate transplant donor directed at the identification of identical or similar combinations of HLA alleles compared with the transplant recipient.
5–65 Describe (A) five ways in which T-cell receptors are similar to immunoglobulins, and (B) five ways in which they are different (other than the way in which they recognize antigen).
5–66 Compare the organization of T-cell receptor α and β genes (the TCRα and TCRβ loci) with the organization of immunoglobulin heavy-chain and light-chain genes.
5–67 T-cell receptors do not undergo isotype switching. Suggest a possible reason for this.
5–68 The role of the CD3 proteins and ζ chain on the surface of the cell is to
- transduce signals to the interior of the T cell
- bind to antigen associated with MHC molecules
- bind to MHC molecules
- bind to CD4 or CD8 molecules
- facilitate antigen processing of antigens that bind to the surface of T cells.
5–69 Which of the following accurately completes this statement: “The function of _______ T cells is to make contact with _______ and _______”? (Select all that apply.)
- CD8; virus-infected cells; kill virus-infected cells
- CD8; B cells; stimulate B cells to differentiate into plasma cells
- CD4; macrophages; enhance microbicidal powers of macrophages
- CD4; B cells; stimulate B cells to differentiate into plasma cells
- All of the above are accurate.
5–70 The immunological consequence of severe combined immunodeficiency disease (SCID) caused by a genetic defect in either RAG-1 or RAG-2 genes is
- lack of somatic recombination in T-cell receptor and immunoglobulin gene loci
- lack of somatic recombination in T-cell receptor loci
- lack of somatic recombination in immunoglobulin loci
- lack of somatic hypermutation in T-cell receptor and immunoglobulin loci
- lack of somatic hypermutation in T-cell receptor loci.
- (i) Describe the structure of an MHC class I molecule, identifying the different polypeptide chains and domains. (ii) What are the names of the MHC class I molecules produced by humans? Which part of the molecule is encoded within the MHC region of the genome? (iii) Which domains or parts of domains participate in the following: antigen binding; binding the T-cell receptor; and binding the T-cell co-receptor? (iv) Which domains are the most polymorphic?
- Repeat this for an MHC class II molecule.
5–72 What is meant by the terms (A) antigen processing and (B) antigen presentation? (C) Why are these processes required before T cells can be activated?
- Describe in chronological order the steps of the antigen-processing and antigen-presentation pathways for intracellular, cytosolic pathogens.
- (i) What would be the outcome if a mutant MHC class I α chain could not associate with β2-microglobulin, and (ii) what would happen if the TAP transporter were lacking as a result of mutation? Explain your answers.
5–74 Which of the following removes CLIP from MHC class II molecules?
- Describe in chronological order the steps of the antigen-processing and antigen-presentation pathways for extracellular pathogens.
- What would be the outcome (i) if invariant chain were defective or missing, or (ii) if HLA-DM were not expressed?
- What is the difference between MHC variation due to multigene families and that due to allelic polymorphism?
- How does MHC variation due to multigene families and allelic polymorphism influence the antigens that a person’s T cells can recognize?
5–77 What evidence supports the proposal that MHC diversity evolved by natural selection caused by infectious pathogens rather than exclusively by random DNA mutations?
5–78 CD8 T-cell subpopulations are specialized to combat _______ pathogens, whereas CD4 T-cell subpopulations are specialized to combat _______ pathogens:
- bacterial; viral
- dead; live
- extracellular; intracellular
- intracellular; extracellular
- virulent; attenuated.
5–79 Which of the following describes the sequence of events involved in processing of peptides that will be presented as antigen with MHC class I?
- plasma membrane →TAP1/2 →proteasome →MHC class I →endoplasmic reticulum
- TAP1/2 →proteasome →MHC class I →endoplasmic reticulum→plasma membrane
- proteasome →TAP1/2 →MHC class I →endoplasmic reticulum →plasma membrane
- proteasome →TAP1/2 →endoplasmic reticulum →MHC class I →plasma membrane
- endoplasmic reticulum →proteasome →MHC class I →TAP1/2 →plasma membrane.
5–80 One type of bare lymphocyte syndrome is caused by a genetic defect in MHC class II transactivator (CIITA), which results in the inability to synthesize MHC class II and display it on the cell surface. The consequence of this would be that
- B cells are unable to develop
- CD8 T cells cannot function
- CD4 T cells cannot function
- intracellular infections cannot be eradicated
- peptides cannot be loaded onto MHC molecules in the lumen of the endoplasmic reticulum.
5–81 Which of the following describes the sequence of events involved in the processing of peptides that will be presented as antigen with MHC class II?
- protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II →endocytosis →plasma membrane
- endocytosis →protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II →plasma membrane
- removal of CLIP from MHC class II →binding of peptide to MHC class II →protease activity →endocytosis →plasma membrane
- binding of peptide to MHC class II →endocytosis →removal of CLIP from MHC class II →protease activity →plasma membrane
- plasma membrane →endocytosis →protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II.
5–82 Which of the following cell types does not express MHC class I?
- dendritic cell
5–83 Which of the following cell types is not considered a professional antigen-presenting cell?
- B cell
- dendritic cell
- all of the above are professional antigen-presenting cells.
5–84 Match the answer on the right that best describes the function on the left. More than one answer may be correct.
|___ a. an intracellular, monomorphic MHC class I isotype whose function is unknown||1. HLA-A, HLA-B, HLA-C|
|__ b. form ligands for receptors on NK cells||2. HLA-E, HLA-G|
|__ c. participate in peptide loading of MHC class II molecules||3. HLA-F|
|__ d. present antigen to CD4 T cells||4. HLA-DP, HLA-DQ, HLA-DR|
|__ e. present antigen to CD8 T cells||5. HLA-DM, HLA-DO|
5–85 Which of the following HLA-DRB genotypes is not possible in an individual? (X: X represents diploid genotype.)
- DRB1: DRB1
- DRB1, DRB3: DRB1, DRB4
- DRB1: DRB1, DRB5
- DRB1, DRB4: DRB1
- DRB3: DRB1, DRB5.
- How many HLA-DR α:β combinations can be made by an individual who is heterozygous at all HLA-DRβ loci, inherits the DRβ haplotype DRB1 from their mother, the DRβ haplotype DRB1, DRB4 from their father, and also inherits different allelic forms of DRA from each parent?
- Repeat this exercise given the same information except that the maternal DRβ haplotype is DRB1, DRB3.
5–87 Which of the following is mismatched?
- peptide-binding motif: combination of anchor residues in a peptide capable of binding a particular MHC haplotype
- MHC restriction: specificity of T-cell receptor for a particular peptide:MHC molecule complex
- balancing selection: maintenance of variety of MHC isoforms in a population
- directional selection: replacement of older MHC isoforms with newer variants
- interallelic conversion: recombination between two different genes in the same family.
5–88 Which is the most likely reason that HIV-infected people with heterozygous HLA loci have a delayed progression to AIDS compared with patients who are homozygous at one or more HLA loci?
- The greater number of HLA alleles provides a wider variety of HLA molecules for presenting HIV-derived peptides to CD8 T cells even if HIV mutates during the course of infection.
- Heterozygotes have more opportunity for interallelic conversion and can therefore express larger numbers of MHC alleles.
- Directional selection mechanisms favor heterozygotes and provide selective advantage to pathogen exposure.
- As heterozygosity increases, so does the concentration of alloantibodies in the serum, some of which cross-react with and neutralize HIV.
- What is the maximum number of MHC class I and class II molecules that a heterozygous individual could theoretically express? Explain your answer. (Ignore the possibility of MHC class II molecules composed of chains from different isotypes.)
- How does this relatively small number of MHC molecules have the potential to bind the huge number of antigenic peptides encountered in the environment, and what features of a peptide determine whether it will be bound by a given MHC molecule?
5–90 (A) Explain the difference between interallelic conversion and gene conversion, and (B) provide an example for both.
5–91 In the context of MHC isoforms, what is the difference between balancing selection and directional selection?
- What are alloantibodies?
- How do alloantibodies arise naturally?
- Why are alloantibodies problematic for transplantation?
- RAG genes do not contain introns, and they function to facilitate the cleavage of double-stranded DNA.
- It has been proposed that the evolution of rearranging antigen-receptor genes began with the insertion of a transposable element into a gene encoding an innate immune receptor. This gene was not only split into two segments, but also became flanked by repetitive DNA sequences donated by the transposon. A later chromosomal rearrangement event translocated the transposase genes to a different chromosome, where they evolved into the ancestral RAG-1 and RAG-2 genes. The repetitive DNA sequences left behind at the original receptor gene location evolved into the recombination signal sequences (RSSs), and the segments of the receptor gene evolved into V and J sequences. Eventually this led to a family of rearranging genes on five chromosomes encoding the immunoglobulin heavy- and light-chain genes, and the T-cell receptor α, β, γ, and δ genes.
5–10 a—1; b—2; c—3; d—5; e—4
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.
5–21 a, c, d
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 do 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.
- 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.
- 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 non-professional antigen-presenting cells.
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).
- (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 co-receptor 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.
5–29 a—F; b—F; c—T; d—F; e—T
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.
5–52 a, d
5–54 b, d
5–59 a, d
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
- Similarities. (1) The T-cell receptor has a similar overall structure to the membrane-bound Fab fragment of immunoglobulin, containing an antigen-binding 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 Vα domain 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 do not undergo somatic hypermutation.
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 1 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 4 J gene segments, each paired with a C gene. The κ locus contains about 35 V gene segments, 5 J segments, and 1 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 heavy-chain locus; both contain V, D, and J gene segments. The TCRβ locus contains about 52 V gene segments, 2 D gene segments, 13 J gene segments, and 2 C genes, encoded on chromosome 7. 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 6 J segments, followed by 9 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 do 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 do not contain numerous alternative C genes.
5–69 a, c, d
- (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 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 HLA-DP, 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 peptide-binding groove formed by the α1 and β1 domains. 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.
- 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 do not bind antigen directly, but rather must recognize antigen bound to MHC molecules on the surface of antigen-presenting cells.
- 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.
- 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 II-associated 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.
- 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 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.
5–84 a—3; b—1, 2; c—5; d—4; e—1
5–86 m and p denote maternal and paternal allotypes, respectively.
- The answer is 6. 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 8. 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.
- 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 6. 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 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.
<<insert Figure A5-89>>
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.
- 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.
5–91 Balancing selection maintains a variety of MHC isoforms in a population, whereas directional selection replaces older isoforms with newer variants.
- 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.
4Th_Ed Test Bank The Immune System – Parham