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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
Q

Allelic exclusion involves changes in ____ structure in the IgH chain locus that limits accessibility to the VDJ recombinase

A

chromatin

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26
Q

True or False?

An individual B cell can express an IgH chain protein encoded by both of the two inherited alleles

A

false, only one

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27
Q

What happens if both alleles undergo nonproductive Ig H gene rearrangements?

A

a survival signal is not generated; cell dies by apoptosis

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28
Q

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?

A

lambda rearrangement

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29
Q

What is the phenomenon of light chain isotype exclusion?

A

only one of the two types of IgL can be expressed

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30
Q

If the rearrangement of k locus is nonproductive, the cell can do what?

A

rearrange the lambda locus to produce a complete IgM molecule

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31
Q

If both k and lambda chains are nonfunctional, what happens to developing B cell?

A

doesn’t receive survival signal; dies

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32
Q

The assembled BCR provides Ag-independent tonic signals that do what?

A

keep the B cell alive and also mediate the shutoff of RAG gene expression that prevents further Ig gene rearrangement

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33
Q

Self Ag recognition by immature B cells induces reactivation of RAG genes and the rearrangement and production of what?

A

a new Ig L chain

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34
Q

What happens if the editing process fails to generate an in-frame productive k IgL?

A

the activated, immature B cell may then go on to rearrange the lambda L chain locus

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35
Q

True or False?

Almost all B cells bearing lambda L chains are cells that were once self-reactive and have undergone receptor editing

A

true

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36
Q

If receptor editing fails, the immature B cells that express high-affinity receptors for self Ags die by apoptosis. This process is called what?

A

negative selection

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37
Q

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

A

B-1; B-2

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38
Q

Following rearrangement of their BCR chain genes and removal of auto reactive cells via central tolerance, immature B2 B cells relocate where?

A

the spleen

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39
Q

The immature B2 B cells that escape the processes of peripheral tolerance differentiate into what?

A

MZ B cells or mature follicular B2 cells

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40
Q

True or False?

Only mature follicular B2 cells upon T-cell-dependent activation develop into long lived plasma cells or memory B cells

A

true

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41
Q

Where do MZ B cells localize? What do they respond to?

A

the splenic marginal zone and respond to blood born Ags

42
Q

Follicular B cells, by contrast, respond to protein Ags in a T cell-dependent manner and progressively undergo what?

A

immunoglobulin isotype switching and affinity maturation

43
Q

B1 Bcells comprise a much smaller population, which predominates where and contributes most of the serum IgM during the early phases of infection

A

the pleural and peritoneal cavities

44
Q

True or False?

Follicualr B cells are self-renewing

A

false; need constant replenishment from bone marrow

45
Q

True or False?

MZ and B1 B cells are self-renewing

A

true

46
Q

Why do B1 cells express limited BCR diversity?

A

TdT is not expressed in the fetal liver

47
Q

B1 cells spontaneously secrete what?

A

IgM

48
Q

Most mature B cells belong to the FBC subset and produce both IgM and IgD with the same what?

A

Ag specificity

49
Q

How is simultaneous expression of IgM and IgD in a single B cell achieved?

A

alternative RNA splicing

50
Q

Selective polyadenylation and alternative splicing allow a B cell to simultaneously produce what?

A

mature mRNAs and proteins of two different H chain isotypes

51
Q

Similar to B1 cells, MZ B cells have BCRs of limited diversity which respond to what?

A

polysaccharide Ags and to generate natural Abs

52
Q

Where can MZ B cells be found?

A

in the spleen as well as in lymph nodes

53
Q

Marginal zone B cells respond very rapidly to blood-borne microbes and differentiate into short-lived what?

A

IgM-secreting plasma cells

54
Q

MZ B cells generally mediate what type of immunity?

A

T-cell independent humoral

55
Q

What is the unique feature of T cell maturation?

A

selection of mature T cells with specificity for self MHC-associated peptide Ags

56
Q

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

A

true

57
Q

Developing T cells in the thymus are called what?

A

thymocytes

58
Q

Maturation of thymocytes mostly occurs in what region of the thymus?

A

the cortex

59
Q

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

A

physical interactions

60
Q

Epithelial cells present in the medulla serve a unique role for the negative selection of developing T cells as what?

A

APCs

61
Q

In regards to the role of the thymus in T cell maturation, bone marrow-derived DCs are present where?

A

the cortico-medullary junction and within the medulla

62
Q

In regards to the role of the thymus in T cell maturation, , macrophages are present primarily within what?

A

the medulla

63
Q

The movement of cells into and through the thymus is driven by what?

A

chemokines

64
Q

CCL25 recognized by CCR9 on precursors, control what?

A

entry into the thymus

65
Q

CCL21 and CCL19 recognized by thymocytes via CCR7 mediate what?

A

the guided movement of developing T cells from the cortex to the medulla

66
Q

Generated T lymphocytes express the sphingosine-1 phosphate receptor and exit the thymic medulla how?

A

following a gradient of sphingosine-1 phosphate gradient into the blood stream

67
Q

IL-7 is produced by epithelial and other stromal cells and induces what?

A

proliferation of thymocytes

68
Q

The rates of cell proliferation and apoptotic death are extremely high or low in cortical thymocytes

A

high

69
Q

95% of thymocytes die by apoptosis due to what 3 reasons?

A
  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
Q

In regards to T cell maturation, the thymic cortex, progenitors of alpha beta T cells express what?

A

TCRs, CD4 and CD8 coreceptors

71
Q

In regards to T cell maturation, negative selection eliminate twice self-reactive T cells in the cortex at what stage?

A

the double-positive stage and also single-positive thymocytes in the medulla

72
Q

TCRs bind self MHC molecules with low affinity and do what?

A

promote survival of thymocytes

73
Q

In regards to T cell maturation, functional and phenotypic differentiation into CD4 or CD8 occurs where?

A

in the medulla

74
Q

Some double-positive cells differentiate into what?

A

regulatory T cells

75
Q

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?

A

double-negative thymocytes and are considered to be pro-T cells

76
Q

Rag1 and Rag2 proteins are first expressed at what stage of T cell development?

A

double-negative stage

77
Q

In rearrangements of TCR genes, which rearrangements of the beta chain locus occur first?

A

the DJ rearrangements

78
Q

In what stage do V(DJ) rearrangements occur?

A

at the pro-T to pre-T stage transition during alpha beta T cell development

79
Q

The pre-T cell receptor associates with what part of the TCR complex in mature T cells?

A

CD3

80
Q

What mediates the development and selection of pre-T cells?

A

the pre-TCR

81
Q

Signals from the pre-TCR mediate the survival of pre-T cells and contribute to what?

A

the largest proliferation during T cell development

82
Q

Pre-TCR signals initiate TCR alpha chain locus recombination and drive what transition in thymocyte development?

A

the transition from the double-negative to double-positive stage of thymocyte development

83
Q

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

A

true

84
Q

True or False?

30% of mature peripheral T cells do express two different TCRs with different alpha chains but the same beta chain

A

true

85
Q

Unsuccessful rearrangements of the TCR alpha gene on both chromosomes lead to what?

A

failure of positive selection and apoptosis

86
Q

Are double-positive thymocytes produced with Ag stimulation?

A

no

87
Q

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

A

cortical epithelial cells

88
Q

In regard to positive selection, death by neglect is when thymocytes whose receptors do not recognize ___ ___ molecules die by apoptosis

A

self MHC

89
Q

The process in which thymocytes whose TCRs bind with low avidity to self peptide-self MHC complexes are stimulated to survive is called what?

A

positive selection

90
Q

What does positive selection ensure?

A

that T cells are self MHC-restricted

91
Q 
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
A

true

92
Q

What is the possible Role of MHC in positive selection?

A

actively induce expression of the correct coreceptor and shut off expression of the other coreceptor

93
Q

True or False?

It is known that double-positive cells go through a stage at which they express high CD8 and low CD4

A

false; high CD4 and low CD8

94
Q

For a class I MHC restricted cell, how strong is the signal when it sees class I MHC?

A

signal is weak due to low levels of CD8 coreceptor

note: these weak signals activate Runx3 that maintains CD8 T cell phenotype

95
Q

For a class II MHC restricted cell, how strong is the signal when it sees class II MHC?

A

signal is strong due to high CD4 levels

note: strong signals activate GATA3, which commits cells toward a CD4 fate

96
Q

High-avidity recognition of self Ags triggers apoptosis and death resulting in ___ ___ of the T cell repertoire?

A

negative selection

97
Q

TCR signaling induces a proapoptotic protein called ___ that plays a crucial role in the induction of mitochondial leakiness (Ca2+) and T apoptosis

A

Bim

98
Q

What three cells found in the thymus are APCs that mediate negative selection?

A

DCs and macrophages in the medulla and medullary thymic epithelial cells

99
Q

How does positive selection driven by weak recognition of self Ags produce a repertoire of mature T cells specific for foreign Ags?

A

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
Q

About __% of developing double-negative T cells become alpha beta T cells

A

90

Immunology (12 decks)

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