Lecture 10 Flashcards
What cytokine stimulates T cells to develop from stem cells?
IL-7
What cytokine stimulates NK cells to develop from stem cells?
IL-15
What stimulates B cells to develop from stem cells?
Unknown
What 3 things can B cells develop into?
Follicular B cells
Marginal zone
B-1 cells
What 2 things can T cells develop into?
Alpha-Beta
Gamma-Delta
Prolymphocytes create large pools with ___ _____
high diversity
Describe T cell development. What is activated in T cells. What does this open up? What does that cause?
Signals activate the Notch1 or GATA3
-GATA3 for alpha-Beta T cells
Opens the TCR Beta gene locus
- Can now undergo rearrangement
- Genes that encode pre-TCR undergo VDJ recombination
Describe B cell development. What do the activating signals activate?
Signals activate Pax-5 and EBF
Genes for B cell development are activated
- RAG-1 and RAG-2
- Surrogate light chains (Pre-BCR)
- Igalpha and IgBeta
H-chain – Chr 14
Kappa-chain (light) – Chr2
Gamma-chain (light)- Chr 22
What are the 3 stages of maturation? Describe each stage.
Prelymphocyte
- Each cell created will have a unique receptor!
- Undergo rearrangement of Ag receptors and selection events
- Pre-BCRs only have IgM heavy chain
- Pre-TCRs only have Beta chain
Immature lymphocyte
- Fully developed
- Naïve (no Ag encountered yet)
Mature lymphocyte
-Ready to go!
For epigenetics, describe Euchromatin, Heterochromatin, Methylation, and Non-coding RNAs (miRNA) and their effects on genes.
Euchromatin- loosely packed and active transcription
Heterochromatin- tightly packed and silenced
Methylation- silence genes
Non-coding RNAs (miRNA)- silence genes
What is Allelic Exclusion? Where does it occur?
Term for how B cells heavy and light chains are expressed
Occurs in bone marrow
What is the inheritance pattern for allelic exclusion? Which one will be used? Which chain is decided first.
Inherited from both maternal and paternal for each
-But only one is expressed
ONLY ONE will be used
- Ex. Maternal H/Paternal L
- Paternal H/Maternal L
- Both Maternal/Both Paternal
H chain is decided first
What are the 3 mechanisms for Ag diversity? Describe the 1st one and the 3rd one.
Somatic Recombination
- Major method
- VDJ rearrangement
mRNA splicing
Junctional diversity
- Loss of nucleotides
- Addition of N and P nucleotides
How many heavy chains are found in the BCR’s? What are they?
How many will be deleted and what will you end up with?
Heavy chains have 4 segments- V, J, D, C
-Multiples of EACH on the heavy chain
All but ONE of these copies deleted
Will end with a singular VDJ sequence
What is the mechism of action for BCR’s?
Single J and single D chosen and DNA deleted between them (done by RAG-1/2)
V segment is chosen and DNA between V and DJ are deleted
Finally, C is chosen (remember inherited not combined)
Pre-mRNA
Will then undergo splicing –> mRNA –> protein of BCR
____ is only expressed form Pro-B to mature B cells (Not in plasma cells)
RAG (Recombination Activating Genes)
During Ig class switching, what do you always start with?
Always start with µ or delta heavy chain –> IgM or IgD formed
What is the mechanism of action for Ig class switching?
Constant region of heavy chains is spliced to another type of Ig gene downstream
Spliced together
Requires AID breaking DNA at Switch regions
During B cell light chain recombination, no matter what the heavy chain is (µ or delta), the light chain will be the ____
Same
Do light chains have D segments?
NO they do not have Diversity segments
What does light chain recombination cause?
A huge amount of diversity
During TCR recombination, describe the alpha chains.
Do not have D segments
During TCR recombination, describe the beta chains.
Have V, D, J and C segments
Are made first
What is the mechanism of action for TCR recombination?
Region between D and J deleted
Region between V and DJ are deleted
Region between VDJ and C are deleted
Uses RAG-1/2
When is Junctional Diversity needed? Describe how it works.
VDJ not enough to combat a strong enough immune response needs Junctional Diversity.
Loss of nucleotides via exonucleases and addition of N and P nucleotides (DURING VDJ recombination)
P nucleotides fill in sites from hairpin cleavage
N nucleotides bind two sections together
What adds P nucleotides and N nucleotides during Junctional Diversity?
P nucleotides- added by RAG
N nucleotides- added by TDT
During the selection process describe checkpoint 1. What is being checked? What is rearranged for B and T cells, respectively? What happens if the rearrangement provides a functional protein? If not, what happens?
Checking of Pre-BCR/TCR
Pro-lymphocytes are rearranged at the heavy chain (B cell) or Beta chain (T cell)
30% rearrangements give functional protein receptor
-Receive survival signals –> Continue to CP2
Those with non-functional receptors–> no survival signal=APOPTOSIS
Describe checkpoint 2 positive selection.
Self-MHC present to T cells with self Ag
Of B cells take up self-Ag
No reaction Maturation
Describe checkpoint 2 negative selection.
Self- Ag presented or taken up by lymphocyte
Reaction to self-Ag
In T cells Immediate response
In B cells –> Undergo receptor editing again
-No reaction –> Immature B cell
-Reaction again to self Ag –> Clonal deletion
What are the 2 types of B cell subtypes?
B1
B2
Describe B1 Characteristics. Where does it develop? What is it limited in? Why?
Where is it found?
What can it secrete?
Develop in fetal liver
Have limited BCR (no TDT in the fetal liver –> no junctional diversity)
Self-renewing
In mucosal sites
Can secrete IgM spontaneously or in rxn to polysaccharides (G+) and lipids
-Contributes to early phases of infection
Describe B2 characteristics. What does it develop from and when?
What are the 2 types? Where are each found?
Arise from bone marrow after birth
Follicular- T cell development
- In circulation and LNs
- Use protein AGs
MZ-independent of T cells, self-renewing
- In spleen (blood-borne path)
- Limited diversity
What are the T cell subtypes? Describe the one that is not commonly found.
Alpha- Beta cells= Typical
If Gamma or Delta is rearranged before Beta is Will become delta-gamma T cell
- Only 1-% of T cells
- Limited diversity (fewer V, J, and D segments)
- In epithelium
