Development of B cells

Question 1

*what are the six phases of B-cell maturation? Include what occurs during each phase

Answer 1

B-cell maturation:

1. Repertoire assembly: generation of diverse and clonally expressed B-cell receptors in bone marrow
2. Negative selection- alteration, elimination or inactivation of B-cell receptors that bind to components of human body.
3. Positive selection- promotion of a fraction of immature B-cells to become mature B cells in secondary lymphoid tissues
4. Searching for infection- recirculation of mature B cells between lymph, blood and secondary lymphoid tissues (can recognize antigen, but has not come across any yet)
5. Finding infection: activation and clonal expression of B cells by pathogen-derived antigen in secondary lymphoid tissues
6. Attacking infection- differentiation to ANTIBODY-secreting plasma cells and MEMORY cells in secondary lymphoid tissue

Question 2

*Describe the six stages of B-cell development in the bone marrow including the names of the cells and what is occurring at each stage regarding H chain genes, L-chain genes and Ig status

Answer 2

B-cell development:
1. Stem cell (no rearrangement occurs in Heavy chain (germline), germline-Light , no Ig status)
2. Early pro-B cell )- aka pre-pro B: Dh and Jh joining (DJ rearrangement, germline, No Ig status)
3. Late-pro B cell- Vh (variable) segment joins DJh (rearrangement in heavy, germline- Light, and no Ig status)
4. Large Pre-B cell: expression of FUNCTIONAL u (mu) heavy chain is made, VDJ rearranged, and Germline L-chain genes), PROLIFERATION?
5. Small-pre- B cell ( LIGHT CHAIN (VJ) rearrangement and assembled with mu chain in ER proliferation
6. Immature B cell- membrane bound- Ig M- associates with Ig-alpha and Ig-Beta (B cell complex formed)
(U heavy chain, lambda or kappa chain, Ig M on surface). VJ light rearranged, and VDJ heavy rearranged.

Question 3

*What is the difference between productive and non-productive rearrangements? Why do you have two chromosomes? What is required for productive rearrangement?

Answer 3

Non-productive rearrangement: cell DOES NOT translate into functional protein (lead to cell death , apoptosis)
Productive rearrangement- COMPLETE and FUNCTIONAL immunoglobulin produced.
2 chromosomes- since there are two chances to make functional immunoglobulin.
productive rearrangements require Rag 1 and 2.

Question 4

*What is the difference between the pre-B cell receptor and B-cell receptor?

Answer 4

Pre- B cell receptor has surrogate light chain, help bind functional light chain and composed of lambda 5 and VpreB proteins
B- cell receptor- mature B cell that has light chain bound and heavy chain.

Question 5

*Describe what occurs with the Rag gene expression during the phases of B-cell development

Answer 5

RAG gene is expressed starting from Early pro- B cell to late pro-B cell. During Large-pre- B cell, RAG is shut down (no gene rearrangement), mu chain is made.
RAG is then reactivated during Light chain rearrangement or small-pre- B cell phase to mature b- cell.

Question 6

*Explain the three fates for self-reactive B-cells

Answer 6

3 fates:
1. Receptor editing-loss of self reactivity
2, Apoptosis- if successive new receptors are self-reactive and gene rearrangements are not possible anymore
3. Anergy- cells become inactivated and unrepsonsive

Question 7

*What is the difference between central and peripheral tolerance

Answer 7

Central tolerance- select for self-antigen present in bone marrow and can undergo receptor editing, anergy and apoptosis
Peripheral tolerance- tolerance to antigens OUTSIDE of bone marrow. NO Receptor editing when encountering self antigen; cell either undergoes APOPTOSIS or ANERGY
B-cell receptor circulates between blood, secondary lymphoid organ, and lymph

Question 8

*Explain which cells express CCR7, CCL21, CCL19, and CXCL13 and their role in B-cell maturation

Answer 8

secondary lymphoid organs are required for maturation of B cells
Chemokine gradients attract B cells to different lymphoid regions
CCL21- expressed in Lymph node cortex and dendritic cells in lymph node. This chemokine attracts immature B cells to HEV.
CCR7- Expressed on B-cell
CCL19- expressed by dendritic cells in lymph nodes (attract B cells to lymph node)
CXCL13- FDCs (Follicular dendritic cells) secrete CXCL13, and this protein attracts B cells into primary follicle.

Question 9

What occurs in B-cell maturation?

Answer 9

B cell precursors in bone marrow acquire functional antigen receptors for immunoglobulin REARRANGEMENT
Also, B cells mature, travel to secondary lymphoid organ for modification of immunoglobulin REPERTOIRE

Question 10

Where do B-cell develop and migrate to?

Answer 10

B cells develop in BONE MARROW, and migrate to SECONDARY organ (Lymph node, Spleen, and Peyer’s patches) to finish development.

Question 11

What is B-cell development in bone marrow equivalent to? Which chain (heavy or light) precedes the other?

Answer 11

B-cell development in bone marrow= Series of immunoglobulin GENE REARRANGMENTs
Heavy chain ALWAYS precedes light chain

Question 12

Describe the components of CD34 cell, CLP, and Pro- B cell.

Answer 12

CD34- characteristic of Bone marrow Stem cell (pluripotent hematopoietic stem); 1 CD34
CLP- Common Lymphoid Progenitor- can become B cell or T cell; contains one CD34, and one CD10.
B-cell precursor- has CD34, CD10, CD127
Pro- B cell is first of the B-cell lineage; can undergo SELF-RENEWAL; where immunoglobulin GENE REARRANGEMENT begins. contains CD19, CD34, CD127 and CD10

Question 13

What is the default pathway in gene rearrangement?

Answer 13

Default pathway- is for cells to die (by apoptosis); unless survival signal is received.

Question 14

Describe the microenvironment and stromal cells present during B-cell development.

Answer 14

B cell development depends on stromal cells that provide a microenvironment for B cells.
Microenvironment: a small, usually distinctly specialized and effectively ISOLATED habitat or environment.
Stromal cells- supporting cells and connective tissue that surrounds other tissues and organs (like Fibroblasts
-They have SPECIFIC contact with B-cells (through adhesion molecules, ligands)
, and SECRETE of Growth factors (stem cell factor (SCF) and IL-7 (interleukin 7).

Question 15

What is the stromal cell composed of?

Answer 15

stromal cell has Kit, a receptor that recognizes , SCF molecules (growth factor) , CAMS, IL-7 (cytokine that is secreted by stromal cells)

Question 16

Explain the process of early pro-B cell becoming a Pre-B cell, including possibility of non-productive rearrangements or productive rearrangement.

Answer 16

Early pro-B cell will undergo D-J rearrangements on 2 chromosomes, to have 2 chances of making a functional immunoglobulin.
if D and J rearrange on both chromosomes and form a Productive rearrangement (complete/functional Ig) the cell will move on to Late Pro- B cell for V-DJ rearrangement and then survival to become Pre- B cells.
-if late pro-B cell has V-DJ rearrangement on second chromosome and forms non-productive rearrangement (no functional protein), the cell will do V-DJ rearrangement on second chromosome (second chance) . If late Pro-B cell forms another non-productive rearrangement on second chromosome, it will be signaled to die by apoptosis (50% of cells).
if late pro-B cell has V-DJ rearrangement on first or second chromosome and has productive rearrangement , it will be signaled to survive and become pre-B cells
(50 % survival and 50% apoptosis).

Question 17

How do the rearrangements differ from Heavy chain and light chain?

Answer 17

Heavy chains- have two chances to make functional immunoglobulin (productive rearrangements)
Light chain- can have many rearrangements (more than 2) to form productive rearrangement and functional protein.

Question 18

What are the two criteria needed for pro-B cell to survive?

What is the surrogate light chain used for?

Answer 18

criteria:
1. Make a mu chain (heavy chain)
2. mu chain must be able to bind to LIGHT chain

Surrogate light chain: has VpreB and lambda 5 extensions; it binds in ER (pre-B cell receptor)

Question 19

How is the functional pre-B cell receptor formed? What is the role of VpreB and lambda5 extensions?

Answer 19

Functional pre-B cell receptor formed:
-signal sent through IgBeta- which shuts down gene rearrangement(RAG expression) and induces proliferation of pro-B cell.
VpreB and Lambda5 extensions- mediate binding to to receptors on stromal cells

Question 20

How many functional mu chains should B-cells have? What happens if B-cells have more than one?

Answer 20

B-cells should only have ONE functional mu chain.
if B-cells have more than one mu chain:
-Pre-B cell receptor assembly- will shut down RAG gene transcription, RAG proteins will be degraded and chromatin structural changes prevent rearrangement.

Question 21

What is allelic exclusion? What is the consequence of no allelic exclusion?

Answer 21

Allelic Exclusion- cell only expresses ONE of its two copies of a gene.
Consequences of NO allelic exclusion- LOW avidity (total binding strength) binding- Heterogenous pentameric IgM
allelic exclusion gives Homogenous b-cell receptors and High avidity binding..

Question 22

What occurs after large pre-B-cell proliferates? What are the events that occur? How many recombinations are necessary?

Answer 22

After large pre-B cell proliferates- you have many SMALL Pre-B cells are created.
-Light chain rearrangement occurs too (V-J rearranging)
-RAG genes are reactivated
ONLY ONE recombination event is necessary- can have successive rearrangement events for light chain.

Question 23

How many light chain loci are there? how many chromosomes? Which Light chain genes undergo rearrangement? What percent of B cells have productive rearrangement?

Answer 23

4 light chain loci
-used for multiple attempts for rearrangement
You can rearrange on 2 chromosomes and 2 genes: Kappa gene (on 1st and 2nd chromosome) and Lambda gene (1st and 2nd chromosome as well).
85% of pre-B cells have productive rearrangment.

Question 24

What happens if you have productive rearrangement during for Kappa and Lambda gene on both chromosomes? what happens if you have nonproductive rearrangement for both kappa and lambda gene on both chromosomes?

Answer 24

productive rearrangement on both chromosomes:
Kappa- immature B cell will express mu and Kappa, IgM
Lambda- immature B cell will express mu and Lamda, IgM
if non-productive rearrangement:
1st try to KAPPA gene on 1st chromosome, then second and move to LAMBDA gene. if non-productive rearrangement on both chromosomes for lambada, cell undergoes APOPTOSIS.

Question 25

What are the major results of Large B-cell expansion?

Answer 25

results:

1. Investment to make heavy chain is NOT lost (85% make functional light chain)
2. DIVERSE population- same mu chain, different Kappa and Beta chains (different antigenic specificities).

Question 26

What are the checkpoints in the bone marrow? What is the significance of these checkpoints?

Answer 26

Checkpoints in Bone marrow, ensure QUALITY of immunoglobulin CHAIN
First checkpoint- PRE- B cell receptor: that selects for functional heavy chains
Second checkpoint: B-cell receptor: selects for functional light chains

Question 27

briefly give description of each stage of B-cell development.

Answer 27

1. Early pro-B cell- commits to B cell lineage
2. Heavy-change Gene rearrangement: generate heavy chain gene diversity in pro-B cell population
3. First checkpoint- pre B cell receptor select functional heavy chain
4. Light-chain gene rearrangement: generates light chain gene diversity in pre-b cell receptor
5. second-checkpoint: B-cell receptor selects for functional light chains
6. Immature B cell- makes functional IgM

Question 28

What proteins are expressed during the different stages of B cell development? What are their functions?

Answer 28

1. FLT3 (tyrosine kinase) - signaling protein expressed in Stem cell
2. Growth factor proteins: Kit (stem cell- late-pro B cells); IL-7 receptor (stem cell- large pre-B cell); CD25 (late pro- B cell to small pre-B cell)
3. RAG 1 and 2- lymphoid specific recombinase, seen in early pro- B cell to late-pro B cell. RAG protein turned off during Large-pre B cell (heavy chain rearrangement) and then RAG activated from small-pre-B cell to Mature B cell
4. lambda 5 and VpreB- surrogate light chain components seen in early pro-B cell to small- small pre-B cell.
5. Signal transduction proteins- Iga and IgBeta, Btk, CD19, CD45R- start from early pro-B cell to Mature B cell
6. Differentiation markers- CD43- early pro- B cell to Large pre- B cell; CD24- Late pro-B cell to mature B cell; BP- Large pre-B cell to Small pre-B cell
7. Transcription factors: E2A and EBF, Pax 5 that are from early-pro B cell to Mature B cell

Question 29

What are the two B cell populations? What makes B1 cells unique? Distinguish between them?

Answer 29

B1 and B2 cells
B1 cells express CD5 (marker for T cells)- 5% of B-cells- LESS DIVERSE, LOW AFFINITY antibodies that bind many different antigens (POLYSPECIFIC); Recognize Bacterial polysaccharides, (not protein recognition)

Question 30

Distinguish between B1 and B2 cell populations? What are their different characteristics?

Answer 30

B-1 cells:
-first produced in fetus, few N regions in VDJ junctions, restricted V-region, primarily located in Peritoneal and pleural cavities, SELF_RENEWING, high spontaneous production of Ig, secretion of IgM > IgG, no requirement for T-cell help, Low somatic hypermutation, Little memory development
B2 cells:
produced AFTER birth, Extensive N regions in VDJ repertoire, DIVERSE V-region repertoire, primarily located in secondary lymphoid organs, Replaced from Bone marrow, low spontaneous production of Ig, secretion of IgG > IgM, required for T cell help, High somatic hypermutation, MEMORY development.

Question 31

What are the primary sites for B- cells? What happens with self-reactive immature B- cells? How is Negative selection involved?

Answer 31

primary sites for B-cells- blood, lymph, secondary lymphoid organs and bone marrow.
Self-reactive immature B cells can binds self antigen- up to 75% of immature B-cells can recognize self-antigen
Negative selection process- starting in the BONE MARROW (stromal cells, hematopoietic cells, soluble blood plasma components)
-only those that don’t recognize self antigens leave bone marrow

Question 32

Describe the process of receptor editing.

Answer 32

Receptor editing:
1. Self antigens ligates immature B cell’s IgM.
2. Immature B-cell continues to rearrange light chain genes
3. Immature B cell makes new light chain and thus an IgM with a different specificity
4. if the new receptor is self-reactive, light chain genes continue rearranging.
5. After successive new receptors are self-reactive, no further rearrangements are possible and immature B cell undergoes APOPTOSIS
Clonal deletion occurs (clones created will be eliminated)
-if the new receptor is NOT self-reactive, the B cell leaves the bone marrow, enters blood and expresses IgD and IgM.

Question 33

What are monovalent self-antigens and where are they seen? what is Anergy? What is the life span of anergic B cells?

Answer 33

monovalent self-antigens: carry ONE epitope
-can be seen in bone marrow or peripheral.
Anergy- when self-reactive B cells that bind monovalent antigens become INACTIVATED and UNRESPONSIVE to the antigen (different than multivalent antigen binding cells)
Anergic B cells have SHORT life span (1-5 days vs 40 days); they make IgD and IgM, but IgM cannot assemble a functional B-cell receptor.

Question 34

During B cell maturation, where do B cells congregate?

Answer 34

B cells congregate in primary LYMPHOID FOLLICLE

Question 35

What are Follicular dendritic cells? what are major events of B cell maturation?

Answer 35

Follicular dendritic cells (FDCs)- specialized stromal cells - NOT of hematopoietic origin, and secrete CXCL13.
During this stage, B-cell matures, detaches and enters circulation
- no antigen encountered- NAIVE B-cells
-antigen encountered- PROLIFERATION and DIFFERENTIATION into plasma cell.
-B cells compete for access to follicular sites to survive.

Question 36

Describe the roles of chemokine in the B-cell maturation process.

Answer 36

1. Chemokine CCL21 attracts Immature B cells to HEV
2. Chemokines CCL21 and CCL19 attract B cells into lymph node
3. CXCL13 (chemokine) attracts B cells in primary follicle (where they congregate)
4. interactions with follicular dendritic cells and cytokines DRIVES maturation of immature B cells
5. Mature B cells recirculate between lymph, blood and secondary lymphoid tissues.

Question 37

Compare and contrast the phases of B cells in bone marrow vs secondary organs.

Answer 37

In Bone marrow- stem cell, early pro-B cell, Late-pro B cell, Large-pre-B cell, Small-pre-B cell, and immature B cell.
In Secondary lymphoid organs

Question 38

Compare and contrast the phases of B cells in bone marrow vs secondary organs.

Answer 38

In Bone marrow- stem cell, early pro-B cell, Late-pro B cell, Large-pre-B cell, Small-pre-B cell, and immature B cell.
In Secondary lymphoid organs;
1. immature B cell leave bone marrow and enter peripheral circulation,
2. alternative splicing- delta and mu chains and gain access to primary lymphoid follicle/matures,
3.Mature naive B cell enters circulation and binds specific antigen in lymphoid tissue, draining infection
4. B-lymphoblast
Alternative splicing to secret Ig, isotype switching and somatic hypermutation,
5. Antibody secreting plasma cell fighting current infection
6. memory cell- preparing for future infection

Question 39

What are thymocytes? What is the Thymic Stroma?

Answer 39

Thymocytes- Immature T- cells

Thymic stroma- network of epithelial cells (like microenvironment)

Question 40

Explain when Thymus becomes developed? what occurs to Thymus as we age?

Answer 40

Thymus is fully developed at BIRTH- and begins to degrade one-year post birth.
Fat gradually takes over area- forming Thymic Involution- reduced production of T cells with age.
Less thymic tissue as we age.

Question 41

Is thymus required for T-cell immunity?

Answer 41

Thymus is NOT required for T-cell immunity once established.

Question 42

Where do T-cells precursors come from and what happens when T cells mature?

Answer 42

T-cell precursors travel from Bone marrow to develop in thymus
Mature T cells leave the Thymus and travel to secondary lymphoid tissues.

Question 43

What occurs in the thymic lobule? What is Double Negative marker? What is the Double positive marker? Which make up majority of cells?

Answer 43

In thymus:
uncommitted progenitors enter- induced to divide an differentiate upon contact with stroma
Double Negative marker (DN1-DN4)- Lack CD4 and CD8 receptors.
Double positive markers- express CD4 and CD8.
Double positive make up majority of cells.

Question 44

What is Flow cytometry used for?

Answer 44

Laser-based technique that examines cells in bone marrow and detects monoclonal antibodies coupled to fluorochromes. It also tries to identify CD4 or CD8 cells.

Question 45

*Understand the concept of thymic involution

Answer 45

Thymic involution- Shrinking of thymus with age; reduction of T- cells.

Question 46

*Know which cells express CD4 and/or CD8 – uncommitted progenitors,
double negative thymocytes, double—positive thymocytes, naïve helper T—
cells, and naïve cytotoxic T—cells

Answer 46

Double positive thymocytes- express CD4 and CD8
-Uncommitted progenitors- CD34 (stem-cell surface marker) and CD44 (adhesion)
- Double Negative Thymocytes- CD2, CD5 (both adhesion), CD127 (cytokine receptor) and CD1A (MHC class I- like molecule)
-RAG complex (recombination
Naive helper T cell- CD4
Naive Cytotoxic helper T cell- CD8

Question 47

*Understand the process of “racing for rearrangements” with regards to α:β
and γ:δ T—cells

Answer 47

both the alpha:beta and gamma:epilson T cells come from common double negative T- cell progentitor.
The double negative thymocytes are programmed to begin rearrangements at the alpha, gamma and B loci at the same time.
Hence, race comes to play as gamma and epsilon loci have to COMPETE with Beta loci in a RACE to make productive gene rearrangements and functional T cell receptor chains.
If thymocyte makes a functional gamma/epsilon receptor before before functional Beta chain, then it commits to gamma/epsilon T cell.
If a functional Beta chain made before gamma/epsilon receptor, then it is incorporated into protein called Pre-T cell receptor.

Question 48

*Understand the role of pTα/surrogate α chain

Answer 48

pTa- surrogate alpha chain that binds to TCR Beta chain in ER to form pre-t cell receptors.
It serves as its own ligand- testing for proper conformation
- it induces LcK activation- signals to STOP rearrangement of Beta, gamma, and Epsilon.
Cells now become pre-T cells.
Lck- lymphocyte tyrosine kinase

Question 49

*Know what occurs with Rag gene expression during the phases of T-cell
development

Answer 49

Rag gene used for gene rearrangement.
RAG gene expression occurs during rearrangement of Beta chain in Double negative phase. RAG expression stops after Beta chain rearrangement and formation of Pre-T cell receptor. It is then reactivated during alpha chain rearrangement to form TCR.

Question 50

*Know what occurs during positive and negative selection during T-cell
development

Answer 50

positive selection- favors survival of T cells that recognize self peptide presented by self MHC molecule
negative selection-eliminates T cells that
bind too tightly to a self peptide presented by a self-MHC molecule and are therefore potentially autoreactive.

Question 51

*Know how Tregs suppress proliferation of CD4 T-cells

Answer 51

Tregs express CD25 on surface- when it binds to self-antigen:MHC complex, it will suppress proliferation of naive CD4 T cells binding to same antigen
CD25 suppresses CD4 T-cell function

Question 52

Why is Notch important? Explain the mechanism. What kind of interaction occurs between Notch and its ligand?

Answer 52

Notch signaling REQUIRED for T-cell development.
Process-
1.Notch 1 (membrane receptor) on the surface of thymocytes bind to it Notch Ligand on thymic epithelium.
2. This induces a protease to cleave the intracellular domain Notch 1 and release it from PM.
3. Soluble domain Notch 1 is then translocated to the nucleus of thymocyte , where it turns on expression of genes essential for T-cell development. This is achieved by removal of co-repressor/repressor genes and activation of co-activator (bound Notch)
Notch and its Ligand have Juxtracrine signaling.

Question 53

What are the two lineages of T-cells. What gives rise to these T cells? What is the major event that occurs with these T-cells?

Answer 53

Two lineages of T-cells: alpha:Beta, gamma:epilson
-determined by expression of T-cell receptor
a common DOUBLE-NEGATIVE T- cell progenitor gives rise to alpha:Beta and gamma:epilson T cells
These T-cells are at a “Race” for rearrangements
and results in the formation of gamma:Epilson or pre-T cell receptor.

Question 54

Compare and contrast what happens if gamma/epsilon functional T cell receptor is made first vs if alpha:beta receptor made first.

Answer 54

if gamma and epsilon chain genes are rearranged first, a gamma:epsilon receptor will assemble and be COMMITTED to gamma:epsilon lineage (stop further rearrangments).
The gamma:epsilon T cell will Mature, leave the thymus and migrate to peripheral tissues in blood

if Beta chain rearranges, a Pre-T cell receptor will form ( stop further rearrangement for beta chain).
this will INDUCE Proliferation and EXPRESSION of CD4 and CD8 cells.
Pre-T cell will resume rearrangement with ALPHA chain and, gamma and epsilon (race continues to whether DP thymocyte makes alpha:beta receptor or gamma:epsilon first)

Question 55

How many steps are needed to become committed gamma:epsilon T cell vs alpha:beta T cell? Which process occurs more frequently?

Answer 55

To be committed gamma:epsilon T cell: ONE step
to be committed alpha:beta T cell: TWO steps needed (including DP thymocyte, alpha rearrangment)
Pre-T cell receptor and rearrangment of Beta and alpha chain, formation of alpha-beta receptor occurs more FREQUENTLY.

Question 56

Describe the process of forming T-cell receptor.

Answer 56

Process:

1. Heterodimer:- you have two heterodimers of Beta chain and pTa chain.
2. The heterodimers will form a Superdimer if Beta chain binds to pTA chain (test)
3. Superdimer interacts with CD3 complex and Zeta chain to form functional Pre-T cell receptor
4. This generates signals that initiate the rearrangement of alpha chain genes and stops the synthesis of pTa.
5. when functional alpha chain is made it associates with the Beta chain to form the T-cell receptor.

Question 57

Explain the different phases of alpha:Beta T cell development and what occurs in each phase.

Answer 57

Alpha:Beta T cell development:
Double Negative Phase
1. Committed T-cell progenitor
2. Rearrangement of Beta, gamma and epsilon chains-
3. First checkpoint- successful rearrangement of B-chain and pTa leads to formation of pre-T Cell receptor
4. Proliferation of pre-T cells- Pre-T cell is signaled to proliferate, creating clones of the same Beta chain
proliferation also leads to expression of CD4 then CD8 cells , forming thymocytes that have both T-cell co-receptors
Double Positive phase:
1. Rearrangement of alpha, Beta, and gamma phase- after proliferation, ceases, Double positive thymocytes makes productive alpha chain gene rearrangement with gamma and epsilon chains and alpha chain made.
2. Second check point- alpha chain is tested for its capacity to bind with Beta chain and assemble T-Cell Receptor.
Single positive phase

Question 58

What kinds of T-cells are positive and negative selection occur? what percent of T-cells will survive selection?

Answer 58

positive and negative selection only for alpha:Beta DP (double positive) T-cells
Only 2% of T-cells survive selection- receptors can interact with MHC I or MHCII receptors made by that individual(positive selection)

Question 59

Explain where the different phases of alpha:beta T cell development occur?

Answer 59

Progenitor cells and proliferation of these cells occur in MEDULLA
Negative selection (occurs first) and positive selection all occur in cortex.
The thymocytes enter medulla, then migrate to cortex for development of T cells. Later they mature in medulla

Question 60

What cells mediate positive selection? Where does positive selection occur? What happens when MHC binds to alpha:beta receptor? What is the binding importance?
What occurs if alpha chain does not bind?

Answer 60

Cortical epithelial cells- mediate positive selection in the thymic cortex- present selfpeptides via MHC I and MCHII molecules. (CD4:MHC II; CD8:MHCI )
MHC molecule that binds to alpha:beta receptor restricts it to that class.
Binding within 3-4 days after receptor expression- SURVIVAL
No binding- APOPTOSIS
Binding will induce decrease in RAG gene transcription and INCREASE in protein DEGRADATION
Receptor can rearrange alpha-chain if it does not bind over 3-4 days

Question 61

How do Double positive thymocytes convert to single positive thymocytes? What occurs once. single positive thymocytes are made?

Answer 61

Double positive thymocytes to single positive thymocytes: based on interaction between T-cell receptor with self-peptide presented by MHC I or MHC II molecules determines whether T cells commit to CD4 or CD8 T cell lineage.
process:
TCR binds self-peptide presented by MHC Class I- leads to CD8 T cell (single + thymocyte)
TCR binds self-peptide presented by MHCII- leads to CD4 T cell (single + thymocyte)
Once single positive thymocytes made (initiate gene expression)
-CD4 Thymocytes have capacity to be T-HELPER cells
CD8 Thymocytes have capacity to be CYTOTOXIC cells.

Question 62

What occurs during Negative selection? What regulates this process? What is AIRE and what does it do?

Answer 62

Negative selection- cells that bind too tightly may be AUTOREACTIVATED- are eliminated.
cells that bind moderately will live, move to next stage.
Negative selection is regulated by numerous cell types-bone-marrow derived dendritic cells and macrophages. AIRE (Autoimmune regulator) is a transcription factor that transcribes many genes encoding tissue specific genes to be expressed by the Subpopulation of epithelial cells in medulla of thymus
Without AIRE: T cells that are specific for tissue-specific antigens are NOT eliminated by negative selection and will attack cells in tissues (seen in autoimmune conditions)

Question 63

Differentiate between whether positive selection or negative selection occurs first in T cells vs B cells.

Answer 63

B-cells: NEGATIVE selection occurs First

T-cells: POSTIVE selection occurs First

Question 64

How long can mature T cells circulate?

Answer 64

Mature T-cells can circulate for many years (undergo replenishment, maintain cells).

Question 65

What kind of tolerance does Negative selection produce?

Answer 65

Negative selection produces central tolerance in T-cell repertoire.

Question 66

Elaborate on the function of Tregs?

Answer 66

T regs (regulatory T cells aka regulatory CD4 T cells)
T regs have receptors that recognize self antigens.
T regs express CD25 on cell surface and use transcription repressor FOXP3 to and will SUPPRESS the activation and proliferation of Naive T cells responding to self antigens

Question 67

What are some similarities and differences between B and T cells?

Answer 67

Similarities: they both undergo negative/positive selection, recirculate through tissues of the body (blood to secondary lymphoid tissues to lymph), both renders self-reactive cells ANERGIC.
Differences: mature T cells are LONGER lived than B cells, B cells-one terminally differentiated state (antibody-secreting plasma cell), T cells- different types of effector cells.