L4-Lymphocyte Development Flashcards
-T and B cell develoment
Where do B-cells develop from?
From haematopoietic stem cells in bone marrow that express PAX5 transcription factor
Is B cell development continuous or non-continuous?
Continuous. It involves the re-arrangement and expression of Ig genes
Outline the process of B cell development
First is the expression of lymphocyte and then B cell specific markers e.g. CD45 then CD15
Why are self reactive B cells removed during this rearrangement and how?
To avoid autoimmunity via negative selection
Describe negative selection in bone marrow
- Generation of B cell receptors: b cell precursors rearranges its Ig genes
- Negative selection occurs so immature b cells bound to self cell surface Ag is removed
- Migration of B cell to lymphoid organs: mature b cell is bound to foreign antigen is activated
- Ab secretion: activated b cells give rise to plasma and memory cells
Which chain rearranges first, the light or heavy?
The heavy chain (Igmu) genes rearrange first and pair with surrogate light chain, which quality checks every chain made
The light chain is the product of what 2 genes?
Vpre B and lambda 5 genes which associates with Ig alpha and beta before moving to cell surface
What is the function of the pre B cell receptor?
It delivers signal to the pre b cell. No Ag is required
What is the effect of the signal from pre-BCR on the cell?
- 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)
What are the expression options for a B cell?
Either a kappa or lamda light chain
*Explain the B cell expression process (4 steps)
Assuming productive join:
- In the early pro b cell DJ rearrangement occurs on both chromosomes
- In late pro b cell V-DJ rearrangements on 1st chromosome, if this fails then attempted on 2nd. If this fails cell is lost
- 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
- Immature B cell is then formed, its expression dependent on where rearrangement was successful
Why do B cells express kappa more than lambda?
Kappa light chain rearranges first
How many attempts does each rearrangement have?
5 as there are 5 further rearrangements at the same locus. However this process is error prone
When does h chain rearrangement stop?
Once pre b cell signalling occurs
What happens to immature B cells that bind multivalent self antigen?
They undergo clonal deletion via apoptosis or recepor editing, where there’s further light chain rearrangements of variable regions
What happens to immature B cells that bind soluble self-antigen?
Cell becmoes anergic (unresponsive) to that antigen
Name similarities between T and B cell development
- originate from bone marrow stem cells
- rearrange receptor genes once in thymus
- express pre T/B receptor
- eliminates self reactive cells by negative selection
Name differences between T and B cell development
- T cells undergo development/ selection in the thymus
What happens to T cell expressing alpha/ beta ?
THey bind with self MHC expressed in thymus via positive slection to avoid excessive response
In 4 steps, how does positive selection of T cells occur?
- 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
- Immature T cells that recognise self MHC recive signals for survial. Those that interact with self antigen are removed
- Mature T cells encounter foreign Ag in peripheral lymphoid and are activated, migrating to lymphoid organs
- Activated T cells migrate to site of infection, proliferate and elimate infection
Where are T cell pre cursors produced?
In bone marrow.
How do T cell precursors develop into thymocytes?
- Precursors migrate to thymus
- TCR genes are rearranged (beta first) and express TCR
- They then acquire other markers e.g. CD3/4/8
- Undergo positive and negative selection
Describe thymus structure
- 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
What kind of cells can be found inside the thymus?
Lymphoid, epithelial, macrophage and dendritic cells
What is the function of pro thymocytes?
- 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
Name markers that express together with TCR
CD3, 4 and 8
What forms the CD3 complex?
Delta, epilsilon, gamma and zeta chain dimers
What is the function of the CD3 complex?
It transmits signal to the T cell nucleus following TCR of p/ MHC**
During rearrangement some thymocytes will express gamma delta TCR rather than alpha beta. Why?
- 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
What actions can double negative thymocytes take?
- Rearrange gamma delta so CD4&8 stay turned off and leave thymus
- Rearrange alpha beta so CD4&8 turn on then becoming single positive
What is a double negative thymocyte?
A T cells that express the αβ (TCR) but doesn’t express CD4, CD8, or NK markers
What actions may a randomly rearranged alpha beta TCR take?
- 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)
Describe the mechanism of positive selection in T cell
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
Describe the mechanism of negative selection in T cells
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
What processes are used in T cell selection, in order?
Positive then negative selection
What is the desired T cell population after selection?
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
Which marker cells recognise Ag in association to MHC class I molecules?
CD4+ SP T cells
Which marker cells recognise Ag in association to MHC class II molecules?
CD8+ SP T cells
