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Immunology > Lymphocyte Development and Ag Receptor Gene Rearrangements Part II (Lec 11) > Flashcards

Lymphocyte Development and Ag Receptor Gene Rearrangements Part II (Lec 11) Flashcards

1
Q

Before birth, B lymphocytes develop from committed precursors where? After birth?

A

in the fetal liver; bone marrow

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2
Q

Immature B cells that express membrane-bound IgM molecules leave the bone marrow to mature further, primarily in the ____

A

spleen

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3
Q

Cells that mature into follicular B cells in the spleen express what immunoglobulins?

A

IgM and IgD on the cell surface

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4
Q

How long does the development of a mature B cell from a lymphoid progenitor take?

A

2 to 3 days

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5
Q

What is the earliest bone marrow cell committed to the B cell lineage?

A

a pro-B cell

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6
Q

True or False?

Pro-B cells produce Ig

A

false; they do not

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7
Q

Rag1 and Rag2 are first expressed in ___ cells, and the first recombination of Ig genes occurs at the H chain locus

A

pro-B

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8
Q

This enzyme, which catalyzes the non-templates addition of junctional N nucleotides, is expressed most abundantly during the pro-B stage when VDJ recombination occurs at the Ig H locus

A

TdT enzyme

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9
Q

The levels of TdT increase or decrease before L chain gene V-J recombination is complete?

A

decrease

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10
Q

Junctional diversity is more prominent in rearrangement of H chain genes or L chain genes?

A

H chain genes

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11
Q

In regards to the pro-B and pre-B stages, the H chain C region exons remain separated from the VDJ complex by DNA containing what?

A

the distal J segments and the J-C intron

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12
Q

In regards to the pro-B and pre-B stages, the rearranged Ig H chain gene is transcribed into what?

A

a primary transcript that includes the rearranged VDJ complex and the C u exons

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13
Q

For a rearrangement to be productive, bases must be what?

A

added or removed at junctions in multiples of three

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14
Q

Approximately __ % of all pro-B cells make productive rearrangements at the Ig H chain locus

A

50

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15
Q

What is the pre-BCR composed of?

A

the u IgH chains and an invariant surrogate IgL chain

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16
Q

In regards to pre-B cell receptors, the surrogate IgL chain is composed of what?

A

V pre-B protein and lambda5 protein

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17
Q

Signals from the pre-BCR are responsible for the largest ___ ____ of B lineage cells in the bone marrow

A

proliferative expansion

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18
Q

Rearrangement of IgH locus is initiated where?

A

pro-B cell stage

note: if successful, it gives rise to the Ig U chain that is expressed on the cell surface in the form of the pre-BCR at the large pre-B cell stage

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19
Q

True or False?

Signaling from the pre-BCR induces clonal proliferation and recombination of IgL genes.

A

true

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20
Q

In-frame IgL gene rearrangements in small pre-B cells result in what?

A

the expression of a complete BCR on immature B cells

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21
Q

What is the first checkpoint in B cell maturation?

A

the expression of the pre-BCR

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22
Q

This kinase is activated downstream of the pre-BCR and is required for delivery of signals from this receptor that mediate survival, proliferation, and maturation at and beyond the pre-B cell stage

A

Bruton’s tyrosine kinase (Btk)

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23
Q

Mutations in the Btk gene result in what disease?

A

x-linked agammaglobullnemia (XLA)

note: characterized by failure of B cell maturation

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24
Q

In regards to the mechanism of Allelic Exclusion, if a u IgH is produced from one chromosome and forms a pre-BCR, this receptor signals to ____ ____ rearrangement of the IgH chain locus on the other chromosome

A

irreversibly inhibit

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25
Allelic exclusion involves changes in ____ structure in the IgH chain locus that limits accessibility to the VDJ recombinase
chromatin
26
True or False? | An individual B cell can express an IgH chain protein encoded by both of the two inherited alleles
false, only one
27
What happens if both alleles undergo nonproductive Ig H gene rearrangements?
a survival signal is not generated; cell dies by apoptosis
28
Following the pre-B stage, each developing B cell initially rearranges a k IgL gene. If productive, it will produce a k IgL protein which associates with the previously synthesized u IgH to produce a complete IgM protein. Production of a k IgL protein prevents what?
lambda rearrangement
29
What is the phenomenon of light chain isotype exclusion?
only one of the two types of IgL can be expressed
30
If the rearrangement of k locus is nonproductive, the cell can do what?
rearrange the lambda locus to produce a complete IgM molecule
31
If both k and lambda chains are nonfunctional, what happens to developing B cell?
doesn't receive survival signal; dies
32
The assembled BCR provides Ag-independent tonic signals that do what?
keep the B cell alive and also mediate the shutoff of RAG gene expression that prevents further Ig gene rearrangement
33
Self Ag recognition by immature B cells induces reactivation of RAG genes and the rearrangement and production of what?
a new Ig L chain
34
What happens if the editing process fails to generate an in-frame productive k IgL?
the activated, immature B cell may then go on to rearrange the lambda L chain locus
35
True or False? | Almost all B cells bearing lambda L chains are cells that were once self-reactive and have undergone receptor editing
true
36
If receptor editing fails, the immature B cells that express high-affinity receptors for self Ags die by apoptosis. This process is called what?
negative selection
37
Most B cells that develop from fetal-liver-derived stem cells differentiate into the __ lineage. B lymphocytes that arise from bone marrow precursors after birth give rise to the ___ lineage
B-1; B-2
38
Following rearrangement of their BCR chain genes and removal of auto reactive cells via central tolerance, immature B2 B cells relocate where?
the spleen
39
The immature B2 B cells that escape the processes of peripheral tolerance differentiate into what?
MZ B cells or mature follicular B2 cells
40
True or False? | Only mature follicular B2 cells upon T-cell-dependent activation develop into long lived plasma cells or memory B cells
true
41
Where do MZ B cells localize? What do they respond to?
the splenic marginal zone and respond to blood born Ags
42
Follicular B cells, by contrast, respond to protein Ags in a T cell-dependent manner and progressively undergo what?
immunoglobulin isotype switching and affinity maturation
43
B1 Bcells comprise a much smaller population, which predominates where and contributes most of the serum IgM during the early phases of infection
the pleural and peritoneal cavities
44
True or False? | Follicualr B cells are self-renewing
false; need constant replenishment from bone marrow
45
True or False? | MZ and B1 B cells are self-renewing
true
46
Why do B1 cells express limited BCR diversity?
TdT is not expressed in the fetal liver
47
B1 cells spontaneously secrete what?
IgM
48
Most mature B cells belong to the FBC subset and produce both IgM and IgD with the same what?
Ag specificity
49
How is simultaneous expression of IgM and IgD in a single B cell achieved?
alternative RNA splicing
50
Selective polyadenylation and alternative splicing allow a B cell to simultaneously produce what?
mature mRNAs and proteins of two different H chain isotypes
51
Similar to B1 cells, MZ B cells have BCRs of limited diversity which respond to what?
polysaccharide Ags and to generate natural Abs
52
Where can MZ B cells be found?
in the spleen as well as in lymph nodes
53
Marginal zone B cells respond very rapidly to blood-borne microbes and differentiate into short-lived what?
IgM-secreting plasma cells
54
MZ B cells generally mediate what type of immunity?
T-cell independent humoral
55
What is the unique feature of T cell maturation?
selection of mature T cells with specificity for self MHC-associated peptide Ags
56
True or False? The thymus involutes with age and is virtually undetectable in post-pubertal humans, resulting in a somewhat reduced output of mature T cells
true
57
Developing T cells in the thymus are called what?
thymocytes
58
Maturation of thymocytes mostly occurs in what region of the thymus?
the cortex
59
Many of the stimuli required for the proliferation and maturation of thymocytes come from other thymic cells. Thymic cortical epithelial cells form a meshwork of long cytoplasmic processes which allow ___ ____ which thymocytes necessary for their maturation
physical interactions
60
Epithelial cells present in the medulla serve a unique role for the negative selection of developing T cells as what?
APCs
61
In regards to the role of the thymus in T cell maturation, bone marrow-derived DCs are present where?
the cortico-medullary junction and within the medulla
62
In regards to the role of the thymus in T cell maturation, , macrophages are present primarily within what?
the medulla
63
The movement of cells into and through the thymus is driven by what?
chemokines
64
CCL25 recognized by CCR9 on precursors, control what?
entry into the thymus
65
CCL21 and CCL19 recognized by thymocytes via CCR7 mediate what?
the guided movement of developing T cells from the cortex to the medulla
66
Generated T lymphocytes express the sphingosine-1 phosphate receptor and exit the thymic medulla how?
following a gradient of sphingosine-1 phosphate gradient into the blood stream
67
IL-7 is produced by epithelial and other stromal cells and induces what?
proliferation of thymocytes
68
The rates of cell proliferation and apoptotic death are extremely high or low in cortical thymocytes
high
69
95% of thymocytes die by apoptosis due to what 3 reasons?
1. failure to rearrange the TCR beta chain gene 2. failure to be positively selected by self MHC molecules 3. self Ag-induced negative selection
70
In regards to T cell maturation, the thymic cortex, progenitors of alpha beta T cells express what?
TCRs, CD4 and CD8 coreceptors
71
In regards to T cell maturation, negative selection eliminate twice self-reactive T cells in the cortex at what stage?
the double-positive stage and also single-positive thymocytes in the medulla
72
TCRs bind self MHC molecules with low affinity and do what?
promote survival of thymocytes
73
In regards to T cell maturation, functional and phenotypic differentiation into CD4 or CD8 occurs where?
in the medulla
74
Some double-positive cells differentiate into what?
regulatory T cells
75
The cortical thymocytes contain TCR genes in their germ line configuration and do not express TCR, CD3, CD4, or CD8. Theses cells are called what?
double-negative thymocytes and are considered to be pro-T cells
76
Rag1 and Rag2 proteins are first expressed at what stage of T cell development?
double-negative stage
77
In rearrangements of TCR genes, which rearrangements of the beta chain locus occur first?
the DJ rearrangements
78
In what stage do V(DJ) rearrangements occur?
at the pro-T to pre-T stage transition during alpha beta T cell development
79
The pre-T cell receptor associates with what part of the TCR complex in mature T cells?
CD3
80
What mediates the development and selection of pre-T cells?
the pre-TCR
81
Signals from the pre-TCR mediate the survival of pre-T cells and contribute to what?
the largest proliferation during T cell development
82
Pre-TCR signals initiate TCR alpha chain locus recombination and drive what transition in thymocyte development?
the transition from the double-negative to double-positive stage of thymocyte development
83
True or False? Pre-TCR signals also mediate beta chain allelic exclusion. In contrast, there is little or no allelic exclusion in the alpha chain locus
true
84
True or False? | 30% of mature peripheral T cells do express two different TCRs with different alpha chains but the same beta chain
true
85
Unsuccessful rearrangements of the TCR alpha gene on both chromosomes lead to what?
failure of positive selection and apoptosis
86
Are double-positive thymocytes produced with Ag stimulation?
no
87
These cells are the only APCs that mediate the positive selection by displaying a variety of self peptides bound to class I and class II MHC molecules
cortical epithelial cells
88
In regard to positive selection, death by neglect is when thymocytes whose receptors do not recognize ___ ___ molecules die by apoptosis
self MHC
89
The process in which thymocytes whose TCRs bind with low avidity to self peptide-self MHC complexes are stimulated to survive is called what?
positive selection
90
What does positive selection ensure?
that T cells are self MHC-restricted
91
``` True or false? A cell that recognizes self class I MHC may randomly differentiate into a CD4 T cell with the wrong coreceptor due to failing to receive survival signals ```
true
92
What is the possible Role of MHC in positive selection?
actively induce expression of the correct coreceptor and shut off expression of the other coreceptor
93
True or False? | It is known that double-positive cells go through a stage at which they express high CD8 and low CD4
false; high CD4 and low CD8
94
For a class I MHC restricted cell, how strong is the signal when it sees class I MHC?
signal is weak due to low levels of CD8 coreceptor note: these weak signals activate Runx3 that maintains CD8 T cell phenotype
95
For a class II MHC restricted cell, how strong is the signal when it sees class II MHC?
signal is strong due to high CD4 levels note: strong signals activate GATA3, which commits cells toward a CD4 fate
96
High-avidity recognition of self Ags triggers apoptosis and death resulting in ___ ___ of the T cell repertoire?
negative selection
97
TCR signaling induces a proapoptotic protein called ___ that plays a crucial role in the induction of mitochondial leakiness (Ca2+) and T apoptosis
Bim
98
What three cells found in the thymus are APCs that mediate negative selection?
DCs and macrophages in the medulla and medullary thymic epithelial cells
99
How does positive selection driven by weak recognition of self Ags produce a repertoire of mature T cells specific for foreign Ags?
positive selection may allow many different T cell clones to survive and differentiate; many of these T cells recognize self peptides with low affinity
100
About __% of developing double-negative T cells become alpha beta T cells
90

Immunology (12 decks)

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