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Immunology Test II > Lymphocyte Development and Antigen Receptor Gene Rearrangement Part I > Flashcards

Lymphocyte Development and Antigen Receptor Gene Rearrangement Part I Flashcards

1
Q

What are the stages of lymphocyte maturation?

A

Stem cell->pro-lymphocyte->pre-lymphocyte->immature lymphocyte->mature lymphocyte

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2
Q

What are the major events during the stem cell and pro-lymphocyte stages of maturation?

A

Growth factor mediated commitment
Proliferation
initiation of antigen receptor gene rearrangment

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3
Q

What are the major events during pre-lymphocyte stage of maturation?

A

Selection of cells that express pre-antigen receptors

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4
Q

What are the major events during immature lymphocyte stage of maturation?

A

Selection of repertoire and acquisition of functional competence

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5
Q

What does the maturation of B and T lymphocytes involve?

A

Involves a series of events that occur in the generative lymphoid organs

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6
Q

The events of maturation include:

A
  1. commitment of progenitor cells to the B or T lymphoid lineage
  2. Proliferation of progenitors and immature (providing a large pool of cells for generation of lymphocytes)
  3. Sequential and ordered rearrangement of Ag receptors genes and the expression of antigen receptor proteins
  4. Selection events
  5. Differentiation of B and T cells into functionally and phenotypically distinct subpopulations
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7
Q

What does the selection events eliminate?

A

Potentially dangerous self-reactive cells

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8
Q

What do pluripotent stem cells give rise to?

A

Distinct B and T lineages

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9
Q

What gives rise to common lymphoid progenitor (CLP)?

A

Hematopoietic stem cells (HSCs)

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10
Q

What do CLPs give rise to?

A

B cells, T cells, and NK cells

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11
Q

What is the commitment to different lineages driven by?

A

By various transcription factors

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12
Q

What can Pro-B cells eventually differentiate into?

A

Follicular (FO) B cells
Marginal zone (MZ) B cells
B-1 cells

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13
Q

What can Pro-T cells commit either to?

A

αβ T cells or γδ T cells

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14
Q

What does the commitment to the B or T lineage depend on?

A

Depends on sequential signaling from several cell surface receptors

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15
Q

What does signaling activate?

A

Activates transcription factors that contribute to the commitment via induction of gene expression and rearrangements of Ag receptor gene

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16
Q

To develop B cells, what locus opens up?

A

The Ig heavy chain locus opens up and becomes accessible to the proteins that will mediate Ig gene rearrangement and expression

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17
Q

To develop αβ T cells, what locus opens up?

A

The TCR β gene locus opens up and becomes accessible for TCR gene rearrangement and expression

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18
Q

What transcription factors commit developing lymphocytes to the T cell lineage?

A

Notch-1 and GATA-3

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19
Q

What are the Notch family of proteins?

A

They are cell surface molecules that are proteolytically cleaved when they interact with specific ligands on neighboring cells

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20
Q

Where does the cleaved intracellular portion of Notch proteins migrate to?

A

To the nucleus and modulate the expression of specific target genes

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21
Q

Notch-1 together with GATA-3 induces what?

A

The expression of genes involved in development of αβ T cells

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22
Q

What do some of the genes expressed by Notch-1 and GATA-3 encode?

A

Some encode components of the pre-TCR and undergo V(D)J recombination

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23
Q

What TFs induce the expression of genes required for B cell development?

A

EBF, E2A, and Pax-5 transcription factors

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24
Q

What genes required for B cell development encode?

A

The Rag-1 and Rag-2 proteins (BCR rearrangement)
Surrogate light chains (pre-B cell receptor)
The Igα and Igβ proteins (the B cell receptor)

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25
Q

What stimulates the proliferation of the committed T and B cell progenitors?

A

Cytokines

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26
Q

What does proliferation ensure?

A

Ensures that a large pool of progenitor cells is available for generation of a high diversity of mature lymphocytes

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27
Q

If a pre-Ag receptor is successfully rearranged, what does it provide?

A

Provides survival signals that select the cell

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28
Q

IL-7 produced by stromal cells in the thymus drives what?

A

The proliferation of human T cell progenitors

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29
Q

What results in X-linked severe combined immunodeficiency disease (XSCID)

A

Mutations in the common γ chain, a protein that is shared by the type I cytokine receptors for several cytokines including IL-2, IL-7, and IL-15.
This blocks T cell and NK cell development, reflecting the requirement for IL-7 in T cell development and IL-15 for NK cells in humans

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30
Q

What cytokine is required for the development of NK cells?

A

IL-15

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31
Q

The mechanisms that makes genes available or unavailable in chromatin are considered to be what?

A

epigenetic mechanisms

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32
Q

How does DNA exist?

A

In chromosomes tightly bound to histones and non-histone proteins, forming chromatin

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33
Q

How may chromatin exist?

A

As relatively loosely packed euchromatin in which genes are available and are transcribed
Or very tightly packed heterochromatin in which genes are maintained in a silenced state

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34
Q

What does the structural organization of portions of chomosomes make some genes available for?

A

Transcription factors to initiate the transcription

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35
Q

What generally silences genes?

A

DNA methylation on cytosine residues

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36
Q

Histone post-translational modifications of the tails of nucleosomes render genes what?

A

Either active or inactive

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37
Q

The silencing of gene expression is done by what?

A

RNA-based mechanisms - by non-coding RNAs

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38
Q

What renders genes either active or inactive?

A

Post-translational acetylation, methylation, or ubiquitination modifications of the histone tails of nucleosomes

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39
Q

What can either enhance or suppress gene expression?

A

Active remodeling of chromatin by proteins called remodeling complexes

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40
Q

What are miRNAs?

A

microRNAs are a class of small noncoding RNAs (~22 nucleotides) that control gene expression at the post-transcriptional level by impairing translation or by promoting degradation of the target messenger RNA (mRNA)

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41
Q

What are required for recruitment of proteins that mediate gene recombination to form function Ag receptor genes?

A

Histone modifications in Ag receptor gene loci

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42
Q

CD4 and CD8 lineage commitment during T cell development depends on what?

A

epigenetic mechanisms (chromosome modifications) that silences the expression of the CD4 gene (heterochromatin state) in CD8 T cells

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43
Q

What do miRNA modulate during T cell development?

A

Gene expression

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44
Q

What results in a preferential loos of regulatory T cells and the consequent development of an autoimmune phenotype?

A

The deletion of Dicer, a key enzyme in miRNA generation

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45
Q

What results in the loss of Dicer in the B lineage?

A

A block at the pro-B to pre-B cell transition, primarily by being permissive for the apoptosis of pre-B cells

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46
Q

What have gene ablation studies revealed?

A

That other specific miRNAs are also involved in other steps in both B and T cell development

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47
Q

What plays a key role in preventing apoptosis of pre-B cells by inhibiting the expression of Bim?

A

miR17-92

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48
Q

What is Bim?

A

a pro-apoptotic Bcl-2 family protein

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49
Q

What targets a Notch receptor that plays important roles in proliferation, differentiation, and survival of T cells?

A

miR-150

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50
Q

How do individuals inherit alleles for L and H chains?

A

They codominantly inherit maternal and paternal sets of alleles for L and H chains

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51
Q

How many VLCL and VHCH alleles is expressed in a single B cell?

A

Only one - either from maternal or paternal

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52
Q

Having only one of the VLCL and VHCH alleles expressed in a single B cells is termed what?

A

This restriction is termed allelic exclusion

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53
Q

What does allelic exclusion also govern?

A

The expression of TCR cells

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54
Q

There are many B cells and T cells, therefore:

A

The maternal and paternal allotypes are expressed equally

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55
Q

Stem cells contain what?

A

Germline Ig and TCR

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56
Q

What are the variable regions of the chains in T and B cells determined by?

A

rearrangement of the DNA

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57
Q

What are the 3 mechanisms of DNA rearrangement?

A

Somatic recombination
mRNA splicing
Junctional diversity

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58
Q

The expression of BCR and TCR is initiated by what?

A

somatic recombination

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59
Q

What is the major mechanism of epitope-specific diversity of BCR and TCR?

A

DNA chromosomal rearrangment

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60
Q

What does DNA chromosomal rearrangement process include?

A

The deletion of DNA/RNA nucleotides and reannealing gene segments

61
Q

What has 2 chromosomes encoding VH and VL chains from maternal and paternal?

A

A signel B cell

62
Q

What part of the H and L chains are highly variable in amino acid sequence?

A

NH-terminus

63
Q

All circulating immunoglobulins of the same isotype have what?

A

limited variability of constant (C) region

64
Q

An individual B cell has many but all ______ BCRs

A

identical

65
Q

How many unlinked gene groups encode immunoglobulins?

A

3
one for μ H-chains (chromosome 14), one for k chains (chromosome 2), and one for λ (chomosome 22) chains each on a different chromosome

66
Q

Within each of the genes the encodes for Ig, there are what?

A

Multiple coding regions (exons) which recombine at the level of DNA to yield a binding site

67
Q

How many variable segements are in each portion of Ig?

A

Heavy chain: 45
k: 35
λ: 30

68
Q

How many variable segments are in each portion of TCR αβ?

A

α: 45

β: 50

69
Q

How many diversity segments are in each portion of Ig?

A

Heavy Chain: 23
k: 0
λ: 0

70
Q

How many diversity segments are in each portion of TCR αβ

A

α: 0

β: 2

71
Q

What is the total potential repertoire with junctional diversity in Ig heavy chain and k?

A

~10^11

72
Q

What is the total potential repertoire with junctional diversity in TCR αβ chains?

A

~10^16

73
Q

What do recombination-activating genes 1 and 2 encode? (RAG)

A

Enzymes performing recombination of BCR and TCR during the process of VDJ recombination

74
Q

The cellular expression of RAG1 and RAG2 is restricted to what?

A

B and T lymphocytes during their developmental stages

75
Q

Each chromosome (maternal and paternal) encoding the components of BCR is trying to be what?

A

The first in genes’ rearrangement

76
Q

Heavy chain has how many separate gene segments?

A

4 separate gene segments in chromosome 14: V, D, J, C

77
Q

What does V, D, J, and C stand for?

A

V - variable
D - diversity
J - joining
C - constant

78
Q

What does each segment for Heavy chain contain?

A

multiple copies of each segment

79
Q

In a single B cell all copies but one are randomly deleted giving what?

A

A unique combination of V-D-J.

80
Q

What does each B cell generate?

A

It’s own V-D-J sequence and thus all B cells are different

81
Q

Immature B cell DNA has multiple copies, after recombination what does the mature B cell DNA have?

A

In mature B cell, each DNA segment is present as a single copy

82
Q

What segment is first chosen in the immature B cell DNA and then whatever is between them is deleted?

A

First, D is chosen and DNA in between D and J is deleted. D and J are fused
D1—–D2———-J1—–J2

83
Q

What segment is secondly chosen in immature B cell DNA?

A

V segment is chosen and DNA between V and DJ is deleted

84
Q

What segment is thirdly chosen in immature B cell DNA?

A

J is chosen and DNA between VDJ and C is deleted

85
Q

What does Cm and Cd stand for?

A

Cm for IgM and Cd for IgD

86
Q

The chance to produce a “productive rearrangement” is:

A

~10%

87
Q

What is productive rearrangement?

A

Rearrangement sequence made without stop codons in the sequence

88
Q

What test will be done for selection of “productive rearrangement”?

A

A test including transcription and translation

89
Q

When “productive rearrangement” is confirmed, what follows?

A

The “competition” is over and the recombination of other segments is STOPPED
How this is done remains UNKNOWN

90
Q

If the VH rearrangement is productive then:

A

B cell proliferates for a while and “takes care” of the VL

91
Q

What recombination rules do VL have?

A

The same as VH

92
Q

There will be a second test for selection of “productive rearrangement”, this time for what sequence?

A

VL

93
Q

What is the final result of B cell DNA rearrangement?

A

Each B cell produces only one kind of VH and VL

94
Q

Because the number of combinations possible is very big, B cells:

A

Produced can recognize any Ag possible

95
Q

How many nucleotides (N) long each segment of the H chains is?

A

V segments = 45
D segments =23
J segments = 6
C segments = 9

96
Q

In a developing B cell, how is the functional VDJ gene produced for the H chain?

A

One of the V segments recombines with one of many D segments, which has already recombined with one of several J segments

97
Q

In each B cell, what happens to the VDJ gene?

A

It is transcribed, spliced and translated into a H-chain protein

98
Q

What does V-D-J recombination brings what close to the enhancer (enh)?

A

Brings promoter sequences (shown as P) close to the enhancer (enh).

99
Q

What does the enhancer promote?

A

Promotes transcription of the rearranged V gene

100
Q

Where does the C region of H chain B cell DNA lie?

A

Downstream of the rearranged V(D)J exon separated by the germline J-C intron

101
Q

The rearranged B cell gene is transcribed to form what?

A

A primary (nuclear) RNA transcript

102
Q

What does subsequent RNA splicing bring together?

A

The leader exon, the V(D)J exon, and the C region

103
Q

What can the B cell mRNA be now translated on after splicing?

A

Translated on ribosomes to produce one of the chains of the antigen receptor

104
Q

What segments make up the k L chain Germ line DNA?

A

35x V segments
5x J segments
1x C segment

105
Q

What segments make up the λ L chain germ line DNA?

A

30x V segments
1x J segment
4x C segments

106
Q

The germline sequence alpha-chain for TCR has what segments?

A

V segment has about 70-80 copies

J segment has 61 copies

107
Q

The germline sequence beta-chain for TCR has what segments?

A

V segment has 52 copies

J segment has 13 (6+7) copies

108
Q

Which TCR chain locus is on chromosome 7?

A

β

109
Q

Which TCR chain locus is on chromosome 14?

A

α

110
Q

Which TCR chain locus have D segments?

A

β

111
Q

Where is junctional diversity generated?

A

At the points between the joining genes

112
Q

What does junctional diversity result from?

A

The loss of nucleotides through the action of exonuclease(s) and from the addition of N and P nucleotides

113
Q

Where are P nucleotides derived from?

A

From the asymmetric opening of hairpin loops

114
Q

What does the opening of the hairpin loops produce?

A

Short, self-complementary single stranded extensions that can be incorporated into junctions, or may alternatively be removed via exonuclease activity

115
Q

What leads to P nucleotides’ palindromic appearance and to their name?

A

The self-complementarity of P nucleotides

116
Q

What are the steps of junctional diversity?

A

RAG cleaves the DNA hairpin at a random site
A single-stranded DNA end is formed
Depending on the site of cleavage, DNA may contain complementary nucleotides
Such stretches of nucleotides are called P nucleotides

117
Q

What is the addition of N nucleotides aided by?

A

Terminal deoxynucleotidyl transferase (TdT)

118
Q

What is the number of possible V-(D)-J combinations in Ig genes?

A

10^6

119
Q

What is the number of possible V-(D)-J combinations?

A

3x10^6

120
Q

During lymphocyte development, what do cell go through?

A

numerous checkpoints at which the developing cells are tested and continue to mature only if a preceding step in the process has been successfully completed

121
Q

When is checkpoint #1?

A

After the production of the first polypeptide chaings of the two-chain Ag receptor is completed

122
Q

When is checkpoint #2?

A

It follows the production of the second polypeptide chain of the Ag receptor once completed

123
Q

What do checkpoints ensure?

A

That only lymphocytes that have successfully completed Ag receptor gene rearrangement processes are selected to mature

124
Q

What does selection eliminate?

A

Potentially harmful self-reactive lymphocytes

125
Q

What do Pre-Ag receptors and Ag receptors deliver during development?

A

Survival signals for their proliferation and continued maturation

126
Q

What are pre-Ag receptors called in B cells and T cells? What do they contain?

A

pre-BCRs and pre-TCRs

They contain only ONE of the two polypeptide chains present in a mature Ag receptor

127
Q

What do pre-BCRs contain?

A

The Ig μ heavy chain

128
Q

What do pre-TCRs contain?

A

The TCR β chain

129
Q

What do B or T cells must undergo?

A

Ag receptor gene rearrangements

130
Q

What is the first Ag receptor gene to be completely rearranged in B cells?

A

The Ig heavy chain (IgH)

131
Q

Cells that successfully rearrange their Ig heavy chain genes express what?

A

The μ heavy chain protein and assemble the pre-BCR

132
Q

Developing T cells that make a ________ synthesize the TCR β chain protein and assemble the pre-TCR

A

productive TCR β chain gene arrangement

133
Q

About ___% of developing B and T cells make productive rearrangements of Ag receptor gene (in-frame rearrangements capable of generating a protein)?

A

30

134
Q

If cells make out-of-frame rearrangements, what happens?

A

The pre-antigen receptors are not expressed, the cells DO NOT receive survival signals and undergo apoptosis

135
Q

What do assembled pre-BCR and pre-TCR provide?

A

signals for survival, proliferation and further development of early B and T lineage cells

136
Q

What B and T lymphocytes proceed to express genes encoding the second chain of the BCR or TCR?

A

Cells with functional pre-Ag receptors

137
Q

If these cells make productive rearrangements of the 2nd chain what happens?

A

They express the complete Ag receptor while they are still immature

138
Q

Which T cells will be eliminated by apoptosis?

A

Those that are potentially harmful because they strongly recognize self-Ags

139
Q

What happens to harmful B cells that strongly recognize self Ags?

A

They are induced to rearrange their 2nd chain of Ag receptors again

140
Q

Lymphocytes that express useful Ag receptors are:

A

Preserved by a process called positive selection

141
Q

What does positive selection ensure in the T cell lineage?

A

Ensures the maturation of CD8 or CD4 T cells whose receptors recognize appropriate self MHC molecules

142
Q

T cells positively selected by self MHC molecules in the THYMUS are able to what?

A

recognize foreign Ag displayed by the same self MHC molecules on APCs in peripheral tissues

143
Q

When does negative selection occur?

A

After Ag receptors are first expressed on developing B and T cells

144
Q

What does negative selection do to B and T cells?

A

It eliminates developing T cells or alters developing B cells whose Ag receptors bind strongly to self Ags present in the thymus or bone marrow

145
Q

What is clonal deletion?

A

A phenomenon when developing T cells with high affinity for self antigens are eliminated by apoptosis

146
Q

Strongly self-reactive immature B cells may be induced to do what?

A

Receptor editing: Make further Ig gene rearrangements and thus evade self-reactivity

147
Q

If B cell receptor editing fails, what follows?

A

The self-reactive B cells die, which is also called clonal deletion

148
Q

What is an important mechanism for maintaining the central tolerance to many self Ags?

A

Negative selection of immature lymphocytes

Immunology Test II (7 decks)

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