CMB2004/L04 Lymphocyte Development

Question 1

What is the role of the Pax5 gene?

Answer 1

Causes cells to stay in bone marrow and become B cells
No Pax5 = migrate to thymus and become T cells

Question 2

What do B cells develop from?

Answer 2

Haematopoietic stem cells in bone marrow

Question 3

Describe briefly how B cells develop.

Answer 3

Rearrangement and expression of Ig genes
Expression of lymphocyte then B cell-specific markers
Removal of self-reactive cells

Question 4

Describe B cell maturation and activation. (4)

Answer 4

B-cell precursor rearranges Ig genes
Immature B cell bound to self cell surface antigen removed from repertoire
Mature B cell bound to foreign antigen activated
Activated B cells give rise to plasma cells and memory cells

Question 5

Describe gene rearrangement in pre-B cells. (3)

Answer 5

H chain genes rearrange first (mew)
Move to cell surface with Iga and IgB expressed with surrogate light chain
Pre-B cell receptor (pBCR)
Light chains rearrange and displace V preB and lambda5 chains
IgM BCR

Question 6

Describe formation of the pre-B cell receptor. (4)

Answer 6

Early pro-B cell expresses no functional proteins
V(H) to DJ(H) rearrangement
Large pre-B cell stops heavy chain gene rearrangement; light chain rearrangement progresses
Immature B cell stops light chain rearrangement
Mature B cell

Question 7

When does rearrangement of D-J(H) start and stop during B cell development?

Answer 7

Early pro-B cell

Question 8

When does rearrangement of V(H)-DJ(H) start and stop during B cell development?

Answer 8

Early pro-B cell to Late pro-B cell

Question 9

When does rearrangement of V(K)-J(K) start and stop during B cell development?

Answer 9

Large pre-B cell to immature B cell

Question 10

When does rearrangement of V(lambda)-J(lambda) start and stop during B cell development?

Answer 10

Small pre-B cell to immature B cell

Question 11

What is the function of pre-BCR?

Answer 11

Delivers signal to pre-B cell that H chain looks functional

Question 12

What does the signal from pre-BCR trigger? (5 steps)

Answer 12

Turns off RAG-1&2 genes
5-6 rounds of cell division
Surrogate light chain expression stops
RAG-1&2 turned on again
L chain rearrangement starts

Question 13

Which kinds of light chain does each individual B cell express?

Answer 13

Either kappa or lambda

Question 14

When will a B cell die?

Answer 14

If it fails to productively rearrange both H and L genes

Question 15

Describe how B pre-B cells can be ‘rescued’. (3)

Answer 15

After successful H chain rearrangement, initial failing to generate non-productive rearrangements of light chain kappa
Up to 10 further rearrangements at same locus attempted
If all are still out of frame, lambda locus will rearrange

Question 16

At which stage in B cell development are RAG1&2 turned off?

Answer 16

Large pre-B cell

Question 17

What occurs to immature B cells that bind soluble self-antigen? (2)

Answer 17

Clonal deletion (apoptosis)
Receptor editing (further light chain rearrangements of variable regions)

Question 18

What happens if a B cell binds soluble self antigen?

Answer 18

Cell becomes unresponsive
Death or inactivation

Question 19

Briefly describe T cell development.

Answer 19

Originate from bone marrow stem cells
Rearrange receptor genes (in thymus)
Express pre-T receptor
Elimination of self-reactive T cells by negative selection

Question 20

Give 2 differences between B cell and T cell development.

Answer 20

T cells undergo development/selection in thymus
T cells expressing aB TCR must bind with self MHC expressed in thymus

Question 21

Describe T cell maturation. (4)

Answer 21

Precursors commit to T cell lineage after Notch signalling and initiate T cell receptor gene rearrangements
Immature T cells that recognise self MHC receive signals for survival; those that interact strongly with self antigen are removed
Mature T cells encounter foreign antigens in peripheral lymphoid organs and are activated
Activated T cells proliferate and eliminate infection

Question 22

Once precursors in the bone marrow have migrated to the thymus, they develop into thymocytes. What then occurs to them?

Answer 22

Rearrange TCR genes (B first) and express TCR
Acquire other markers
Undergo positive and negative selection

Question 23

Describe the structure of the thymus.

Answer 23

Bi-lobed organ in anterior mediastinum
Each lobe divided into many lobules
Each lobule has outer cortex and inner medulla

Question 24

Describe T cell maturation in the thymus.

Answer 24

Pro-thymocytes enter cortex via blood vessels from bone marrow
Once inside, thymocytes rearrange TCR genes
First rearrange TCRB genes
Expressed along with pre-T cell receptor
Cells proliferate and rearrange TCRa genes

Question 25

What is expressed by T cells in the thymus?

Answer 25

TCR with CD3
CD4 and CD8

Question 26

What is required for TCR expression?

Answer 26

CD3 complex
Transmits signal to T cell nucleus following TCR recognition of p/MHC

Question 27

Highlight some key differences between a/B and gamma/delta TCR.

Answer 27

Gamma/delta do not express CD4/CD8 markers
Less diversity than aB receptor
Expressed on separate T cell population
Lineage commitment depends on which genes are first to rearrange successfully

Question 28

Give 3 possible features of T cells expressing a randomly arranged a/B TCR.

Answer 28

Recognising self MHC plus peptide from foreign Ag
recognise self MHC plus peptide from self Ag (autoimmunity)
Not be able to recognise self-MHC (useless)

Question 29

Describe positive selection of T cells.

Answer 29

Occurs when double-positive T cells recognise MHC on cortical epithelial cells in thymus
Weak or no binding - dies
Moderate or strong binding - lives

Question 30

Describe negative selection of T cells.

Answer 30

TCR binding to MHC/self-peptide with high affinity causes T cell to die by apoptosis (clonal deletion)
Moderate binding - lives
Tight binding - dies

Question 31

When and where does positive and negative selection occur in the thymus?

Answer 31

Cortex - positive selection
Moves to Medulla - negative selection

Question 32

What percentage of cells survive thymic selection?

Answer 32

<5%

Question 33

Give 3 features of T cells that survive thymic selection?

Answer 33

Express TCR capable to binding self MHC
Are depleted of self-reactive cells

Question 34

Which T cells recognise Ag in association with:
a) MHC class I
b) MHC class II?

Answer 34

a) CD8+ T cells
b) CD4+ T cells