[EXAM 2] Lecture 4 (Development of B cells and T cells) Flashcards
1
Q
What is the phase 1 in B-cell precursors?
A
Repertoire Assembly; generation of diverse and clonally expressed B-cell receptors in the bone marrow (Lecture 1, Slide 2)
2
Q
What is Phase 2 in B-cell precursor?
A
Negative selection; alteration, elimination or inactivation of B cell receptors that bind to components of the human body (Lecture 1; slide 2)
3
Q
What is Phase 3 in B-receptor precursor?
A
Positive selection, promotion of fraction of immature B cells to become mature B-cells in the secondary lymphoid tissues
4
Q
What is Phase 4 in B-cell precursor?
A
Searching for Infection
- recirculation of mature B cells between lymph., blood, and secondary lymphoid tissues
5
Q
What is Phase 5 of B cell precursors?
A
Finding Infection; activation and clonal expansion of B cells by pathogen derived antigen in secondary lymphoid tissues
6
Q
What is Phase 6 of B-cell precursor?
A
Attacking infection
- differentiation to antibody secreting plasma cells and memory B cells in secondary lymphoid tissue
7
Q
What happens to B cells in bone marrow?
A
acquire functional antigen receptors immunoglobulin rearrangement
8
Q
Where do B cells develop?
A
Bone marrow and migrate to secondary organs (eg. lymph node, spleen, peyers patches)
9
Q
What is CD34?
A
a characteristic of bone marrow stem cell
10
Q
What is CD10?
A
A characteristic of common lymphoid progenitor cells along with CD34
11
Q
What is CD127?
A
A characteristic of B-cell precursor along with CD10 and CD34
12
Q
What is CD19?
A
A characteristic of CD19 along with CD127, CD10, CD34
13
Q
What is a Pro-B-cell?
A
first of B cell lineage
self renewal
immunoglobulin gene rearrangement begins
14
Q
What always precedes the formation of the light chain?
A
heavy chain
15
Q
What phase includes D and J joining?
A
Early pro-B cell
16
Q
What phase includes the V segment joining DJ?
A
Late pro-B cell
17
Q
What phase includes the expression of functional heavy chain?
A
Large pre-B cell
18
Q
What phase includes the light chain rearrangement and assembled with heavy chain in ER proliferation?
A
Small pre-B cell
19
Q
What phase includes membrane bound IgM-association with Ig alpha and Ig beta ( B cell receptor complex formed)
A
Immature B cell
20
Q
What happens to nonproductive rearrangements?
A
do not get translated into functional protein
21
Q
What happens to productive rearrangements?
A
They form complete and functional immunoglobulin
22
Q
What is the benefit of having two chromosomes?
A
Allows two chances to make functional immunoglobulin
These productive rearrangments require Rag1 and Rag2
23
Q
What is the default pathway for pro-B cells?
A
To die via apoptosis unless survival signal received
24
Q
Where does early pro-B cell H chain gene rearrange?
A
D-J rearangements on both chromosomes
25
Where does late pro-B cell heavy chain gene arrangement occur?
V-DJ rearrangement on first chromosome (productive rearrangement)
26
Where does nonproductive rearrangement occur?
in,
- V-DJ rearrangement on second chromosome
- signaled to die by apoptosis
27
Where does productive rearrangement occur?
signaled to survive and become pre-B cells: 50% of cells
28
What are the two criteria of pro-B cell to survive?
- able to make a heavy chain
| - heavy chain must be able to bind to light chain
29
What are surrogate light chains?
VpreB and lambda5
- binds in ER (pre B cell receptor)
- mediate binding to receptors on stromal cells
30
How are functional pre-B cell receptors formed?
signal sent through IgB-shuts down gene arrangement and induces proliferation of pro-B cell
31
What is allelic exclusion?
-cell only expresses one of its two copies of a gene
gives homogenous B-cell receptors with
high avidity binding
32
What are consequences of no allelic exclusion?
low avidity binding-heterogeneous pentameric IgM
-overall decrease in specificity (pg 957 Section 6-4)
33
Describe pre-B cell receptor assembly?
Signals through the IgB subunit shuts down RAG gene transcription, RAG proteins degraded, and chromatin structural changes to prevent rearrangement
34
We do not want B cells with more than one functional ___________ chain?
heavy
35
What is another term for nonproductive rearrangment?
not spliced
36
Are successful rearrangements possible at the immunoglobulin light chain loci?
Yes
37
What are the steps for pre-light chain development?
1. ) Must HAVE FUNCTIONAL HEAVY CHAIN
2. ) AFTER LARGE PRE-B- CELL PROLIFERATES-(have many small pre-B cells)
3. ) light chain rearrangement now occurs
4. )RAG GENES ACTIVATED
5. ) ONLY 1 RECOMBINATION EVENT NECESSARY-CAN HAVE SUCCESSIVE REARRANGEMENT EVENTS
38
WHAT ARE THE RESULTS OF LARGE B-CELL EXPANSION?
1. ) INVESTMENT TO MAKE HEAVY CHAIN IS NOT LOST (85% MAKE FUNCTIONAL LIGHT CHAIN)
2. ) DIVERSE POPULATION - SAME HEAVY CHAIN, BUT DIFFERENT KAPPA AND BETA CHAINS (DIFFERENT ANTIGENIC SPECIFICITIES
39
HOW MANY LIGHT CHAIN LOCI ARE PRESENT IN THE PRE-B CELL?
4 LIGHT CHAIN LOCI
1. ) REARRANGE KAPPA GENE ON FIRST CHROMOSOME
2. ) REARRANGE KAPPA GENE ON SECOND CHROMOSOME
3. ) REARRANGE LAMBDA GENE ON FIRST CHROMOSOME
4. ) REARRANGE LAMBDA GENE ON SECOND CHROMOSOME
-MULTIPLE ATTEMPTS LFOR REARRANGEMENT
40
WHERE ARE CHECKPOINTS FOUND IN BONE MARROW TO ENSURE QUALITY OF IMMUNOGLOBULIN CHAIN?
1. ) AFTER HEAVY CHAIN GENE REARRANGEMENT (selects for functional heavy chains)
2. ) AFTER LIGHT CHAIN GENE REARRANGEMENT (select for functional light chains)
41
What happens to an pro-B cell if no pre-B cell receptors form?
apoptosis
42
What happens to the pre-B cell if it can not bind to the B cell receptor?
apoptosis
43
What stage of immunoglobulin chain production does the B cell commit to B-cell lineage?
early pro-B cell
44
What stage of immunoglobulin chain production generates heavy chain gene diversity in the pro-B cell population?
Heavy-chain gene arrangement
45
What stage of immunoglobulin chain production generates light-chain gene diversity in the pre-B cell population
Light chain gene rearrangement
46
What stage of immunoglobulin chain production makes functional IgM?
Immature B cell
47
What are Kit, IL-7 receptor, and CD25 have in common?
They are all growth factor receptors found in the Early pro-B cell, late pro-B cell, and large pre-B cell respectively
48
Where is RAg 1 and 2 most common in?
Late Pro B cell and immature B cells
49
Where are surrogate light chain components most commonly found?
Early pro-B, Late pro-B, large pre-B, and small pre-B
50
What are the names of the B-cell populations?
B-1 and B-2
51
What is the function of B-1 cells?
express CD5 (a marker for T cells)-~5% of B-cells-less diverse, low-affinity antibodies that bind many different antigens (polyspecific)-recognize bacteria polysaccharides, not protein recognition
(Lecture 1, slide 16)
52
What are the characteristics of B-2 cells?
- first produced after birth
- extensive VDJ junctions
- Diverse V region repertoire
- primary location: secondary lymphoid organs
- replaced from bone marrow
- low spontaneous production of immunoglobulin
- Secrete more IgG than IgM
- required for T cell help
- somatic hypermutation occurs
- memory development: yes
53
What are the primary sites for B cells?
-blood, lymph, secondary lymphoid organs, bone marrow
54
What is the selection process for B-cell?
Self reactive immature B-cells bind self-antigen-up to 75% of immature B cells can recognize self antigen
55
What is the negative selection process?
starting in bone marrow
| - only those that don't recognize self-antigens leave the bone marrow
56
What is receptor editing?
retained and given a chance to rearrange receptor
57
What is clonal deletion?
Successive new receptors are self-reactive. No further rearrangements are possible and the immature B cell undergoes apoptosis
58
What are monovalent self-antigens?
antigens that carry one epitope
59
What is anergy?
Self-reactive B cells that bind monovalent antigens to become inactivated and unresponsive to the antigen(different than the multivalent antigen-binding B-cells)
**DO not DIE but cannot bind to any antigen***
60
What are anergic B cells?
Short life span (1-5 days vs 40 days)- make IgD and IgM, but IgM cannot assemble a functional B cell receptor
61
What are the three fates of self-reactive B cells?
1. ) receptor editing- loss of reactivity (can happen when recognize more than 1 self antigen)
3. ) apoptosis
3. ) anergy (w/ monovalent antigen)
62
What is central tolerance?
tolerance to self-antigens that are generated in B cell and T cell populations during their development in the primary lymphoid tissues
63
In the periphery, how would you describe the antibody receptors?
receptor editing is no longer an option upon encountering self antigen now-die by apoptosis or become anergic
64
What is peripheral tolerance?
tolerance to antigens outside the bone marrow
65
Where do B cells circulate?
blood, secondary lymphoid organs, and lymph
66
What is CCL21?
chemokine expressed in lymph node cortex and dendritic cells in lymph nodes
- attracts immature B cells to HEV
67
What is CCR7?
expressed on B-cell
68
What is CCL19?
chemokine expressed by dendritic cells in lymph nodes
69
Where do B-cells congregate?
primary lymphoid follicle
70
What is CXCL13?
chemokine that attracts B cells into the primary follicle
71
What drives the maturation of immature B cells?
interactions with follicular dendritic cells and cytokines
72
What are follicular dendritic cells (FDCs)?
specialized stromal cells-NOT of hematopoietic origin-secrete CXCL13 (not dendritic cells)
73
What type of B cells do not encounter antigen?
naive B cells
74
How do B cells try to survive?
they compete for access to follicular sites to survive
75
What are thymocytes?
immature T-cells
76
What is the Thymic stroma?
network of epithelial cells
77
When is the thymus fully developed? And when does it degrade?
at birth, and degrade by year post-birth
78
What is thymic involution?
fat gradually take over area-reduced production of T cells with age
79
Is the Thymus required for T-cell immunity once estabished?
not required
80
What is the correlation between age and fat?
fat takes up thymus tissue as age increases
81
What is the fate of uncommon progenitor?
induced to divide and differentiate upon contact with stroma
82
What is the double negative mean?
lack CD4 and CD8
83
What is flow cytometry?
uses laser light source to excite particles to be detected by scatter detector
84
What is a single cell suspension graph?
Shows distribution of CD8 and CD4 cells in thymus.
- not a lot of only CD4 and only CD8 cause they are leaving the thymus
- higher number of both because they are originated in the thymus
85
What receptors are found in uncommitted progenitor cells?
CD34 and CD44
86
What receptors are found in the double negative thymocyte committed to the double negative thymocyte committed to the T cell lineage
```
CD2
CD5
CD127
CD1A
Rag Complex
```
87
What is the function of CD2?
Adhesion and signaling
88
What is the function of CD5? `
adhesioon and signalijng
89
What is the function of CD127?
cytokine receptor
90
What is the function of CD127?
Cytokine receptor
91
What is the function of CD1A?
MHC class I-like molecule
92
Wha is the function of CD4 and CD8 (general terms)?
co-receptors
93
What does RAG complex function as?
recombinase
94
What signal is required for T-cell development and why?
Notch signaling because it is a quick response b/c of intracellular domain is transcription factor
- this drives proliferation of cells
95
What are the two lineages of T-cells?
alpha:Beta and gamma:beta expression of TCR determines
"Race" for rearrangments
Results in gamma: delta or pre-T cell receptor
96
What determines the committed alpha:beta and gamma:delta?
"Race" for rearrangment
97
How can a committed alpha:beta T cell be formed?
If the beta rearrangement occurs forming an uncomiited double-positive thymocyte
then, alpha wins the rearrangment and forms alpha:beta T cell
98
How are committed gamma:delta T cells formed?
when a beta arrangment "wins" forming uncommitted double-positive thymocyte B-chain
then, delta wins reaarangment and forms it
99
What rearrangement occurs more often?
Beta chain to form uncommitted double positive thymocyte
100
What is pTalpha?
- surogate alpha chain-binding occurs in ER
- serves as its own ligand-testing for proper conformation-induces Lck activation-signals to stop rearrangment beta,gamma, and delta
- calls are now pre T cells
101
What receptor (exclusively spoken about in class) does not occur in single positive ?
Notch 1 receptor
102
What is the differences between medullary cells and dendritic cells?
Medullary epithelial cells are of thymic origin
| Dendritic cells are of bone marrow origin
103
What is a double positive thymocyte?
Contains CD4 and CD8 receptors
104
Where does positive and negative selection occur?
alpha:beta doiuble positive T cells
105
What is an example of positive selection?
only 2% of T cells will survive selection-receptors can interact with MHC I or II receptors made by that individual (Lecture 1, slide 38)
106
Where does the T cell selection process occur?
Cortex
107
Where does cell proliferation originate in?
medulla
108
What cells mediate positive selection in the thymic cortex and how are they able to do that?
Cortical epithelial cells,
| present self peptides via MHC I and II molecules (CD4:MHC II, CD8: MHC I)
109
How long do alpha:beta cells have to bind to an epithelial cell before they have to perform apoptosis?
Binding within 3-4 days
110
How does binding of alpha:beta T cell affect Reg gene?
it decreases RAG gene transcription and increase in the protein degradation
111
T/F: Receptors rearrange the B-chain if it doesn't bind over the 3-4
false: Receptors can rearrange alpha chain if it doesnt bind over the 3-4 days
112
What is the cytotoxic receptor?
CD8
113
What is the T-helper receptor?
CD4
114
What is negative selection and what is it regulated by and what is it transcribed by?
* **cells that bind too tightly may be autoreactive-and are eliminated
* **regulated by numerous cell types-bone marrow- derived dendritic cells and macrophages
* ** transcribed by the transcription factor autoimmune regulator (AIRE) (subpopulation of epithelial cells in medulla of thymus express tissue specific genes)
115
What are Tregs?
***Cells that express CD25 on surface-when bind self-antigen: MHC complex, will suppress proliferation of naive CD4 T-cells binding the same antigen
116
T/F: Mature T cells are long lived and circulate for many years?
True
