L4-Lymphocyte Development

Question 1

Where do B-cells develop from?

Answer 1

From haematopoietic stem cells in bone marrow that express PAX5 transcription factor

Question 2

Is B cell development continuous or non-continuous?

Answer 2

Continuous. It involves the re-arrangement and expression of Ig genes

Question 3

Outline the process of B cell development

Answer 3

First is the expression of lymphocyte and then B cell specific markers e.g. CD45 then CD15

Question 4

Why are self reactive B cells removed during this rearrangement and how?

Answer 4

To avoid autoimmunity via negative selection

Question 5

Describe negative selection in bone marrow

Answer 5

1. Generation of B cell receptors: b cell precursors rearranges its Ig genes
2. Negative selection occurs so immature b cells bound to self cell surface Ag is removed
3. Migration of B cell to lymphoid organs: mature b cell is bound to foreign antigen is activated
4. Ab secretion: activated b cells give rise to plasma and memory cells

Question 6

Which chain rearranges first, the light or heavy?

Answer 6

The heavy chain (Igmu) genes rearrange first and pair with surrogate light chain, which quality checks every chain made

Question 7

The light chain is the product of what 2 genes?

Answer 7

Vpre B and lambda 5 genes which associates with Ig alpha and beta before moving to cell surface

Question 8

What is the function of the pre B cell receptor?

Answer 8

It delivers signal to the pre b cell. No Ag is required

Question 9

What is the effect of the signal from pre-BCR on the cell?

Answer 9

• turns off RAG 1&2 genes
• triggers 5/6 rounds of cell division
• expression of surrogate L chain stops
• turns RAG 1&2 genes on again
• L chain arrangement starts (RAG genes needed for rearrangement)

Question 10

What are the expression options for a B cell?

Answer 10

Either a kappa or lamda light chain

Question 11

*Explain the B cell expression process (4 steps)

Answer 11

Assuming productive join:

1. In the early pro b cell DJ rearrangement occurs on both chromosomes
2. In late pro b cell V-DJ rearrangements on 1st chromosome, if this fails then attempted on 2nd. If this fails cell is lost
3. In pre b cell kappa gene rearranged on first chromosome. If this fails then attempted on 2nd. If this fails too this is tried again with lamda. If this too fails the cell is lost
4. Immature B cell is then formed, its expression dependent on where rearrangement was successful

Question 12

Why do B cells express kappa more than lambda?

Answer 12

Kappa light chain rearranges first

Question 13

How many attempts does each rearrangement have?

Answer 13

5 as there are 5 further rearrangements at the same locus. However this process is error prone

Question 14

When does h chain rearrangement stop?

Answer 14

Once pre b cell signalling occurs

Question 15

What happens to immature B cells that bind multivalent self antigen?

Answer 15

They undergo clonal deletion via apoptosis or recepor editing, where there’s further light chain rearrangements of variable regions

Question 16

What happens to immature B cells that bind soluble self-antigen?

Answer 16

Cell becmoes anergic (unresponsive) to that antigen

Question 17

Name similarities between T and B cell development

Answer 17

• originate from bone marrow stem cells
• rearrange receptor genes once in thymus
• express pre T/B receptor
• eliminates self reactive cells by negative selection

Question 18

Name differences between T and B cell development

Answer 18

• T cells undergo development/ selection in the thymus

Question 19

What happens to T cell expressing alpha/ beta ?

Answer 19

THey bind with self MHC expressed in thymus via positive slection to avoid excessive response

Question 20

In 4 steps, how does positive selection of T cells occur?

Answer 20

1. Precurosrs commit to T cell lineage following notch signalling, initiating receptor gene rearrangement. T cell progenitors develop in bone marrow and migrate to thymus where development is completed by gene rearrangement
2. Immature T cells that recognise self MHC recive signals for survial. Those that interact with self antigen are removed
3. Mature T cells encounter foreign Ag in peripheral lymphoid and are activated, migrating to lymphoid organs
4. Activated T cells migrate to site of infection, proliferate and elimate infection

Question 21

Where are T cell pre cursors produced?

Answer 21

In bone marrow.

Question 22

How do T cell precursors develop into thymocytes?

Answer 22

1. Precursors migrate to thymus
2. TCR genes are rearranged (beta first) and express TCR
3. They then acquire other markers e.g. CD3/4/8
4. Undergo positive and negative selection

Question 23

Describe thymus structure

Answer 23

• its is a bilobed organ in the anterior mediastinum (mid thorax)
• each lobe is divided into many lobules
• each lobule has outer cortex and inner medule

Question 24

What kind of cells can be found inside the thymus?

Answer 24

Lymphoid, epithelial, macrophage and dendritic cells

Question 25

What is the function of pro thymocytes?

Answer 25

- They first rearrange TCR beta genes, then pre TCR alpha (invariant) the pre T cell receptor. - These alpha cells proliferate and then rearrange TCR alpha genes

Question 26

Name markers that express together with TCR

Answer 26

CD3, 4 and 8

Question 27

What forms the CD3 complex?

Answer 27

Delta, epilsilon, gamma and zeta chain dimers

Question 28

What is the function of the CD3 complex?

Answer 28

It transmits signal to the T cell nucleus following TCR of p/ MHC**

Question 29

During rearrangement some thymocytes will express gamma delta TCR rather than alpha beta. Why?

Answer 29

- gamma delta T cells don't express CD4/8 markers (less diversity than alpha beta receptor) - gamma delta recognises different Ag - expressed on seperate T cell population, with majortity in epithelial tissues at mucosal surface

Question 30

What actions can double negative thymocytes take?

Answer 30

- Rearrange gamma delta so CD4&8 stay turned off and leave thymus - Rearrange alpha beta so CD4&8 turn on then becoming single positive

Question 31

What is a double negative thymocyte?

Answer 31

A T cells that express the αβ (TCR) but doesn't express CD4, CD8, or NK markers

Question 32

What actions may a randomly rearranged alpha beta TCR take?

Answer 32

- recognise self MHC plus peptide from foreign Ag (immunity) - recognise self MHC plus peptide from self Ag (autoimmunity) - not be able to recognise self MHC (useless lmao)

Question 33

Describe the mechanism of positive selection in T cell

Answer 33

Selection of cells which recognise self MHC: -occurs when double +ve T cells recognise MHC on cortical epithelial cells. apoptosis if not recognised -rearrangement gives TCR repertoite and +vely selected cells move to medulla

Question 34

Describe the mechanism of negative selection in T cells

Answer 34

Selection of cells tha recognise self MHC on thymic dendritic/ macrophage cells with high affintiy - these cells may induce autoimmunity if not removed - TCR binding causes clonal deletion via apoptosis

Question 35

What processes are used in T cell selection, in order?

Answer 35

Positive then negative selection

Question 36

What is the desired T cell population after selection?

Answer 36

T cells with low affinity for self peptide and MHC as they will have high afiinity or self MHC when presenting peptides derived from pathofens

Question 37

Which marker cells recognise Ag in association to MHC class I molecules?

Answer 37

CD4+ SP T cells

Question 38

Which marker cells recognise Ag in association to MHC class II molecules?

Answer 38

CD8+ SP T cells