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 THE IMMUNE SYSTEM, FOURTH EDITION
CHAPTER 7: THE DEVELOPMENT OF T
LYMPHOCYTES
© 2015 GARLAND SCIENCE

7–1 In which of the following ways does the developmental pathway of α:β T cells differ
from that of B cells? (Select all that apply.)
a. Their antigen receptors are derived from gene rearrangement processes.
b. When the first chain of the antigen receptor is produced it combines with a surrogate
chain.
c. Cells bearing self-reactive antigen receptors undergo apoptosis.
d. MHC molecules are required to facilitate progression through the developmental
pathway.
e. T cells do not rearrange their antigen-receptor genes in the bone marrow.

7–2 Which of the following cell-surface glycoproteins is characteristic of stem cells, but stops
being expressed when a cell has committed to the T-cell developmental pathway?
a. CD2
b. CD3
c. CD25
d. CD34
e. MHC class II.

7–3 Which of the following processes is not dependent on an interaction involving MHC
class I or class II molecules? (Select all that apply.)
a. positive selection of α:β T cells
b. intracellular signaling by pre-T-cell receptors
c. negative selection of αβ T cells
d. peripheral activation of mature naive T cells
e. positive selection of γ:δ T cells.

7–4 If a double-negative thymocyte has just completed a productive β-chain gene

rearrangement, which of the following describes the immediate next step in the development of
this thymocyte?
a. A pre-T-cell receptor is assembled as a superdimer.
b. Rearrangement of γ- and δ-chain genes commences.
c. Expression levels of RAG-1 and RAG-2 are elevated.
d. The linked δ-chain genes are eliminated.
e. This cell will inevitably differentiate into a committed γ:δ T cell.

7–5 All of the following cell-surface glycoproteins are expressed by double-negative

thymocytes undergoing maturation in the thymus except _____. (Select all that apply.)
a. CD2
b. CD5

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c. CD127 (IL-7 receptor)
d. CD34
e. CD1A
f. CD4.

7–6 _____ is a T-cell-specific adhesion molecule expressed before the expression of a

functional T-cell receptor while the thymocytes are still in their double-negative stage of
development.
a. CD4
b. CD8
c. CD25
d. CD2
e. CD3.

7–7 Which of the following is mismatched:

a. double-negative CD3– thymocytes: cortico-medullary junction
b. double-negative CD3– thymocytes: subcapsular zone
c. double-positive CD3+ thymocytes: cortico-medullary junction
d. cortical epithelial cells: subcapsular regions
e. dendritic cells: cortico-medullary junction.

7–8 After interaction with thymic stromal cells, _____, a glycoprotein not expressed by the
uncommitted progenitor cell is activated in developing thymocytes. (Select all that apply.)
a. CD2
b. CD34
c. CD5
d. CD127 (IL-7 receptor)
e. CD44.

7–9 Which of the following statements about Notch 1 is correct? (Select all that apply.)
a. Notch 1 is expressed on thymic epithelial cells.
b. In the absence of Notch 1 expression, T cells can complete their differentiation.
c. Notch 1 is to T-cell development as Pax-5 is to B-cell development.
d. Notch 1 contains two distinct domains, one of which is proteolytically cleaved and
becomes a transcription factor in the nucleus.
e. The extracellular domain of Notch 1 must interact with a ligand on thymic epithelium to
initiate cleavage and separation of the Notch 1 extracellular and intracellular domains.

7–10 Which of the following is the first stage of T-cell receptor gene rearrangement in α:β T
cells?
a. Vα→Dα
b. Dα →Jα
c. Vβ→ Dβ
d. Dβ→Jβ
e. Vα→Jα.

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7–11 Which of the following is the first T-cell receptor complex containing the β chain to
reach the cell surface during the development of T lymphocytes?
a. γ:β:CD3
b. β:CD3
c. α:β:CD3
d. β:CD44
e. pTα:β:CD3.

7–12 The T-cell receptor β-chain locus can undergo successive gene rearrangements to rescue
unproductive V(D)J rearrangements.
A. What aspects of gene segment rearrangement at the TCRβ locus make this possible?
B. Can the immunoglobulin heavy-chain locus, which is also composed of V, D, and J
segments, undergo successive rearrangements? If not, give the reasons for the difference.

7–13 Indicate which of the following statements is true (T) or false (F).
a. __ Immature T cells failing to successfully recombine a β-chain locus die by apoptosis.
b. __ Apoptotic T cells are ingested by medullary epithelial cells.
c. __ Allelic exclusion of the T-cell receptor α and β chains is effective; therefore, all T
cells express only one T-cell receptor on the cell surface.
d. __ T-cell receptor rearrangements have many features in common with immunoglobulin
rearrangement, including the use of the RAG-1 and RAG-2 genes.
e. __ The expression of the pre-T-cell receptor is required in order to halt β-, γ-, and δ-chain
rearrangements.

7–14 Genetic deficiencies in all of the following would impair the development of a fully
functional T-cell repertoire except
a. RAG-1 or RAG-2
b. Notch1
c. Pax-5
d. IL-7 receptor (CD127)
e. TAP-1 or TAP-2.

7–15
A. What is Notch1?
B. Which cells express the ligand of Notch1?
C. How does the interaction between Notch1 and its ligand mediate T-cell development?

7–16 There are many parallels between the development of B cells and T cells. Identify the
incorrectly matched counterpart in B cells (left) versus T cells (right).
a. VpreBλ5: pTα
b. Igα/Igβ:CD3
c. Pax-5: FoxP3
d. multiple κ and λ light-chain gene rearrangements: multiple α-chain gene rearrangements.

7–17 _______ of thymocytes is necessary to produce a T-cell repertoire capable of interacting

with self-MHC molecules.

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a. positive selection
b. negative selection
c. apoptosis
d. receptor editing
e. isotype switching.

7–18 Which of the following statements are true of a T cell that expresses two α chains (and
thus two different T-cell receptors) as a result of ineffective allelic exclusion of the α chain
during rearrangement? (Select all that apply.)
a. Engaging either of the T-cell receptors on MHC molecules of the thymic epithelium will
result in positive selection.
b. One of the T-cell receptors will be functional while the other will most probably be non-
functional.
c. If either T-cell receptor binds strongly to self-peptides presented by self-MHC molecules,
the thymocyte will be negatively selected.
d. One of the T-cell receptors may be autoreactive but escape negative selection because its
peptide antigen is present in tissues other than the thymus.
e. Subsequent gene rearrangements may give rise to a γ:δ T-cell receptor.

7–19 Once a thymocyte has productively rearranged a β-chain gene, which of these event(s)
can occur subsequently? (Select all that apply.)
a. β binds to pTα and is expressed on the cell surface with the CD3 complex and ζ chain.
b. Rearrangement of β-, γ-, and δ-chain genes ceases as a result of the suppression of
expression of RAG-1 and RAG-2.
c. The pre-T cell proliferates and produces a clone of cells all expressing an identical β
chain.
d. Expression of CD34 and CD2 gives rise to double-positive thymocytes.
e. α-, γ-, and δ-chain loci rearrange simultaneously.

7–20 Which of the following statements regarding positive selection is correct?

a. All subsets of developing T cells undergo positive selection before export to the
peripheral circulation.
b. T-cell receptor editing is linked to the process of positive selection.
c. Positive selection results in the production of T cells bearing T-cell receptors that have
the capacity to interact with all allotypes of MHC class I and class II molecules, and not just
those of the individual.
d. Positive selection ensures that autoreactive T cells are rendered non-responsive.
e. If there is a genetic defect in AIRE, then T-cell development is arrested as positive
selection commences.

7–21 Thymocytes that are not positively selected

a. undergo genetic reprogramming and differentiate into a different cell type
b. are exported to the periphery, where they are phagocytosed by macrophages
c. make up about 98% of developing thymocytes and die by apoptosis in the thymic cortex
d. are eliminated because of their reactivity with self antigens
e. try out different β chains to acquire reactivity with self-MHC molecules.

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7–22 If the process of positive selection did not occur, then
a. a condition resembling immune dysregulation, polyendocrinopathy, enteropathy, X-
linked syndrome (IPEX) would develop
b. a condition resembling autoimmune polyendocrinopathy–candidiasis–ectodermal
dystrophy (APECED) would develop
c. naive T cells would be unable to undergo differentiation in secondary lymphoid tissues
d. malignant transformation would be more likely because of the accumulation of multiple
mutations
e. only a very small percentage of circulating T lymphocytes would be able to become
activated.

7–23 Immediately after positive selection

a. the thymocyte reaches maturity and is exported to the periphery
b. RAG proteins are degraded and are no longer synthesized
c. receptor editing commences to eliminate reactivity against self antigens
d. the developing thymocyte acquires a double-negative phenotype
e. expression of pTα is repressed.

7–24 Allelic exclusion occurs for all of the following except

a. T-cell receptor α genes
b. T-cell receptor β genes
c. B-cell receptor heavy-chain genes
d. B-cell receptor κ-chain genes
e. B-cell receptor λ-chain genes.

7–25
A. Explain two ways in which the expression and processing of self antigens in thymic
epithelium differs from the expression and processing of self antigens outside the thymus.
B. In what way is the thymic situation advantageous for the purposes of negative selection?

7–26 Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is

caused by a defect in
a. cathepsin L
b. a transcription factor that regulates tissue-specific gene expression in the thymus
c. the production of regulatory CD4 T cells
d. FoxP3
e. T-cell receptor gene rearrangement.

7–27 Identify which of the following describes how antigen processing and presentation of self
antigens by thymic epithelial cells differs from that of antigen-presenting cells in peripheral
tissues. (Select all that apply.)
a. Thymic epithelium expresses MHC class I molecules but not MHC class II molecules.
b. Thymic epithelium uses cathepsin L for proteolytic degradation of self proteins.
c. Thymic epithelium expresses MHC class II molecules but not MHC class I molecules.

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d. Thymic epithelium uses the transcription factor AIRE to activate thymic expression of
tissue-specific genes.
e. Thymic epithelium expresses transcription repressor protein FoxP3.

7–28 Match the immunodeficiency in Column A with its corresponding cause or consequence
in Column B.

Column A Column B
___a. IL-7 receptor deficiency 1. absence of functional AIRE
___b. DiGeorge syndrome 2. absence of functional MHC class I or
MHC class II molecules
___c. IPEX 3. absence of T cells because of signaling
defects by thymic stromal ells
___d. Bare lymphocyte syndrome 4. absence of functional FoxP3
___e. APECED 5. absence of T cells due to absence of
thymus

7–29 All of the following types of protein are processed and presented by macrophages in the
thymus except _____ proteins.
a. tissue-specific
b. soluble proteins from extracellular fluids
c. ubiquitous proteins
d. proteins made by macrophages
e. proteins derived from other cells that macrophages phagocytose.

7–30 Healthy individuals have approximately ____ of CD4 T cells compared with CD8 T cells.
a. one quarter the number
b. half the number
c. equal numbers
d. twice the number
e. four times the number

7–31 The surrogate light chain operating during pre-B-cell development is made up of
VpreB:λ. Its expression with μ on the pre-B-cell surface is an important checkpoint in B-cell
maturation. Name the T-cell analog of VpreB:λ5 and discuss how it is functionally similar.

7–32 Double-negative thymocytes initiate rearrangement at the _____ locus (loci) before all
other T-cell receptor genes.
a. γ and δ
b. β
c. α and β
d. α, γ, and δ
e. β, γ, and δ.

7–33 The function of negative selection of thymocytes in the thymus is to eliminate

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a. single-positive thymocytes
b. double-positive thymocytes
c. alloreactive thymocytes
d. autoreactive thymocytes
e. apoptotic thymocytes.

7–34 In T cells, allelic exclusion of the α-chain locus is relatively ineffective, resulting in the
production of some T cells with two T-cell receptors of differing antigen specificity on their cell
surface.
A. Will both these receptors have to pass positive selection for the cell to survive? Explain
your answer.
B. Will both receptors have to pass negative selection for the cell to survive? Explain your
answer.
C. Is there a potential problem in having T cells with dual specificity surviving these
selection processes and being exported to the periphery?

7–35 Mature B cells undergo somatic hypermutation after activation, which, after affinity
maturation, results in the production of antibody with a higher affinity for antigen than in the
primary antibody response. Suggest some reasons why T cells have not evolved the same
capacity.

7–36 MHC class II deficiency is inherited as an autosomal recessive trait and involves a defect
in the coordination of transcription factors involved in regulating the expression of all MHC
class II genes (HLA-DP, HLA-DQ, and HLA-DR).
A. What is the effect of MHC class II deficiency?
B. Explain why hypogammaglobulinemia is associated with this deficiency.

7–37 As we age, our thymus shrinks, or atrophies, by a process called involution, yet T-cell
immunity is still functional in old age.
A. Explain how T-cell numbers in the periphery remain constant in the absence of continual
replenishment from the thymus.
B. How does this differ from the maintenance of the B-cell repertoire?

7–38
A. What is the role of regulatory CD4 T cells (Treg)?
B. How can Treg be distinguished from other non-regulatory CD4 T cells?

7–39 Which of the following statements is correct?

a. In adults the mature T-cell repertoire is self-renewing and long-lived and does not require
a thymus for the provision of new T cells.
b. T cells and B cells are both short-lived cells and require continual replenishment from
primary lymphoid organs.
c. The human thymus is not fully functional until age 30, at which time it begins to shrink
and atrophy.
d. In DiGeorge syndrome the bone marrow takes over the function of the thymus and
produces mature peripheral T cells.

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e. None of the above statements is correct.

7–40 Individuals with a defective autoimmune regulator gene (AIRE) exhibit

a. DiGeorge syndrome
b. autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED)
c. severe combined immunodeficiency (SCID)
d. MHC class I deficiency
e. MHC class II deficiency.

7–41 Giulia McGettigan was born full term with a malformed jaw, cleft palate, a ventricular
septal defect, and hypocalcemia. Within 48 hours of birth she developed muscle tetany,
convulsions, tachypnea, and a systolic murmur. A chest X-ray showed an enlarged heart and the
absence of a thymic shadow. Blood tests showed severely depleted levels of CD4 and CD8 T
cells; B-cell numbers were low but within normal range. Parathyroid hormone was undetectable.
Fluorescence in situ hybridization of the buccal mucosa revealed a small deletion in the long arm
of chromosome 22. Giulia failed to thrive and battled chronic diarrhea and opportunistic
infections, including oral candidiasis and Pneumocystis jirovecii, the latter infection causing her
death. Giulia most probably had which of the following immunodeficiency diseases?
a. AIDS
b. DiGeorge syndrome
c. bare lymphocyte syndrome
d. chronic granulomatous disease
e. hyper IgM syndrome.

7–42 The human thymus begins to degenerate as early as one year after birth. This process is
called ______ and is marked by the accumulation of ___ once occupied by thymocytes.
a. thymectomy; dendritic cells
b. involution; fat
c. differentiation; γ:δ T cells
d. negative selection; γ:δ T cells
e. involution; thymic stroma.

7–43
A. What is immunological tolerance?
B. What is the general name for the antigens against which the immune system is normally
tolerant?

ANSWERS
7–1 d, e

7–2 d

7–3 b, e

7–4 a

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7–5 d, f

7–6 d

7–7 a

7–8 a, c, d

7–9 c, d, e

7–10 d

7–11 e

7–12
A. Successive gene rearrangement is possible at a TCRβ locus because there are two sets of
D, J, and C gene segments downstream of the cluster of V gene segments:
(Vβ)n…Dβ1…(Jβ1)n…Cβ1…Dβ2…(Jβ2)n…Cβ2. If a first rearrangement involving Dβ1 and a Jβ1
segment is unproductive, an upstream V gene segment can rearrange to the second D gene
segment and an associated J segment. If this is unproductive, no more rearrangements can be
made.
B. The answer is no. The heavy-chain locus has the following configuration: (V)n-
heptamer…23 spacer…nonamer…nonamer…12 spacer… heptamer-(D)n-heptamer…12
spacer…nonamer…nonamer… 23 spacer…heptamer (J)n…Cμ. After the first DJ rearrangement,
the intervening D segments between the chosen D and J will be deleted. After VDJ
rearrangement, the D segments that lie between the chosen V and DJ will be deleted. Therefore,
no unrearranged D segments remain after these two rearrangement events. V and J cannot
rearrange directly because the recombination signal sequences are not paired appropriately and
do not follow the 23/12 rule; rather, they both contain 23-bp spacers in their recombination
signal sequences. Successive gene rearrangement is thus not possible at a heavy-chain locus.

7–13 a—F; b—F; c—F; d—T; e—T

7–14 c

7–15
A. Notch1 is a membrane-bound receptor found on thymocytes that participates in the
regulation of early T-cell development.
B. Its ligand (Notch ligand) is a membrane-bound protein on the surface of thymic epithelial
cells.
C. After binding of the extracellular domain of Notch1 to the extracellular portion of Notch
ligand, the intracellular domain of Notch1 is released by proteolysis and subsequently
translocates to the nucleus. In the thymocyte nucleus, this domain forms a transcription factor
complex that displaces repressor proteins from genes involved in T-cell development and
initiates transcription of these genes by recruiting transcription activator proteins.

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7–16 c

7–17 a

7–18 a, b, c, d

7–19 a, b, c, e

7–20 b

7–21 c

7–22 e

7–23 b

7–24 a

7–25
A. (i) As well as expressing their own thymus-specific self antigens, medullary epithelial
cells in the thymus produce a transcription factor called autoimmune regulator (AIRE), which
causes several hundred genes normally expressed in other tissues to be expressed in these cells.
The proteins can then be processed to form self peptides that will be presented by MHC class I
molecules. (ii) The thymic epithelium uses different proteases for self-protein degradation;
cathepsin L is used for peptide production instead of cathepsin S, which is used by other cell
types.
B. Generating a more comprehensive repertoire of self peptides in the thymus increases the
types of potentially autoreactive T cell that are removed from the peripheral T-cell repertoire
during negative selection.

7–26 b

7–27 b, d

7–28 a—3; b—5; c—4; d—2; e—1

7–29 a

7–30 d

7–31 The analog of VpreB:λ5 in developing T cells is the protein preTα(pTα), which combines
with the T-cell receptor β chain, the first of the two T-cell receptor chains to be expressed, to
form the pre-T-cell receptor. The β chain, like the immunoglobulin heavy chain, contains V, D,
and J segments. pTα also binds CD3 and ζ components to this complex, and the assembly of the
complete complex induces T-cell proliferation and the cessation of rearrangement at the TCRβ

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loci (leading to allelic exclusion). Formation of the analogous pre-B-cell receptor complex of
VpreB:λ5 and heavy chain with Igα and Igβ in B cells similarly prevents further rearrangement
of the heavy-chain loci.

7–32 e

7–33 d

7–34
A. Only one of the receptors will have to be positively selected for the cell to get the
survival signals necessary for it to pass on to the next stage. Even if the other receptor does not
react with self MHC this will have no effect on the cell.
B. In contrast, both receptors will have to pass the negative selection test for the T cell to
survive, because if only one of them fails it, the cell will die.
C. Yes. Imagine this situation. The T cell with dual specificity could be activated
appropriately during a genuine infection by a professional antigen-presenting cell plus foreign
antigen 1 using T-cell receptor 1. But that same T cell, because it is now an activated effector T
cell, would also be able to respond to a second peptide, which might be a self peptide, using T-
cell receptor 2, without requiring the co-stimulatory signals that only professional antigen-
presenting cells deliver. Thus it could cause a reaction against a self tissue, either directly, if it is
a CD8 cytotoxic T cell, or indirectly, if it is a CD4 T cell, by activating potentially autoreactive
B cells.
Furthermore, interferon-γ produced in the response against foreign antigen 1 could
activate nonprofessional antigen-presenting cells nearby, inducing the expression of MHC class
II with presentation of the self peptide above. Effector T cells with T-cell receptor 2 could make
an autoimmune response against it.

7–35 Because T cells drive almost all immune responses, once they have been activated their
receptors must continue to recognize the exact complex of foreign antigen and MHC molecule
(which does not itself change) that activated them. Because of this requirement for dual
recognition (MHC restriction), somatic hypermutation would be more likely than not to change
the T-cell receptor to make it unable to recognize either the peptide or the MHC molecule, or the
combination of both, thus rendering it unable to give help to B cells or to attack infected cells.
This would destroy both the primary immune response and the development of immunity. Even
changes that simply increased the affinity of the T cell for its antigen would have no real
advantage, because it would not make the immune response any stronger or improve
immunological memory in the same way that affinity maturation of B cells does. Also, if somatic
hypermutation changed the specificity of the T-cell receptor so that it now recognized a self
peptide, this could result in an autoimmune reaction. These considerations do not apply to B
cells, because they require T-cell help to produce antibody and will only receive it if their B-cell
receptor still recognizes the original antigen.

7–36
A. MHC class II deficiency affects the development of CD4 T cells in the thymus. If the
thymic epithelium lacks MHC class II, positive selection of CD4 T cells will not take place. CD8
T cells are not affected because MHC class I expression is unaffected by this defect.

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B. To produce antibody, B cells require T-cell help in the form of cytokines produced by
CD4 TH2 cells. Low immunoglobulin levels (hypogammaglobulinemia) in MHC class II
deficiency are attributed to the inability of B cells to proliferate and differentiate into plasma
cells in the absence of TH2 cytokines.

7–37
A. After thymic atrophy or thymectomy, T cells in the periphery self-renew by cell division
and are long lived.
B. B cells are short lived and replenish from immature precursors derived from the bone
marrow.

7–38
A. Treg suppress the proliferation of naive autoreactive CD4 T cells by secreting inhibitory
cytokines. This inhibitory action requires that both the Treg and the other CD4 T cell are
interacting with the same antigen-presenting cell.
B. Unlike non-regulatory CD4 T cells, Treg express CD25 on the cell surface and the FoxP3
transcriptional repressor protein.

7–39 a

7–40 b

7–41 Rationale: The correct answer is b. Depletion of T cells, but not of B cells, and the
absence of a thymic shadow on the X-ray are critical clues. Development of both CD8 and CD4
T cells is affected in this patient because the thymus is the primary lymphoid organ required for
T-cell development. Bare lymphocyte syndrome affects either CD8 (type I) or CD4 (type II), but
not both. Although patients without a thymus succumb to infections also common in individuals
with AIDS, this option can be ruled out because Giulia lacks CD8 T cells, a condition not seen in
AIDS patients. Chronic granulomatous disease is a defect of neutrophil, not T-cell, function.

7–42 b

7–43
A. Immunological tolerance is the mechanism that operates to ensure that lymphocytes do
not contain antigen receptors specific for host components. This is achieved through a process
involving the removal of self-reactive T and B cells called negative selection. Both T and B cells
are removed by apoptosis after the engagement of T-cell receptors and immunoglobulins,
respectively, if the interaction with their ligands is especially strong. The consequence is the
removal of autoreactive lymphocytes that could cause damage to healthy, uninfected cells and
tissues.
B. Self antigens.

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