L9 Flashcards
Where are immune cells tested for self reactivity?
Primary lymph organs - bone marrow & thymus
Name the early stages of B and T cell development.
Common lymphoid progenitor Pro T/B Pre T/B Immature T/B Mature T/B
Do T cells gain CD4/8 or CD3 markers first? When do each of these happen?
Get both CD4&8 @ immature
Then lose one of those
+ CD3high as mature cell
Do B cells get CD19 or IgM markers first? When do each of these happen?
CD19 1st as proB
Igm low as immature –> high as mature
What signals determine a CLP daughter cell’s fate as a T or B cell?
T cell - NOTCH receptor-ligand interactions
B cells - induce EBF (early B cell factors) & Pax5 TFs
What kinds of mutations might lead to adult leukemia and lymphoma?
Chromosome translocations and point mutations to NOTCH or Pax5/EBF
What is a way that variable region rearrangement is limited to early T.B cells only?
Unique expression of RAG1/2 & Tdt
List the order in which T cell genes are rearranged.
Gamma/delta
Beta
Alpha
Generate mature receptors: alpha-beta, gamma-delta
List the order in which B cell genes are rearranged.
Heavy 1st
- DJ
- VDJ
Light (gamma or kappa) second
Where do you find gamma-delta T cells?
Small intestine
Epidermis
Uterine epithelium
What is allelic exclusion?
For TCR beta gene and heavy chain (B cell)
= expression of only 1 allele’s product
If unsuccessful gene rearrangement round 1 of heavy chain (B cell) or beta (T cell)
Non-fxnal pre-receptor
Cell gets to re-try rearrangement on the same gene’s allele on the OTHER chromosome
Successful - good to go
Not successful - kill the cell
Why do you do allelic exclusion?
Ensure monoclonal expression in the beta or heavy chain
What are the 2 requirements for allelic exclusion?
Sequential rearrangement
Pre T/BCR signaling to feedback to V gene accessibility
What happens if a TCR has low avidity to self antigen?
Aka weak/no TCR signal to self
Kill cell
What happens if a TCR has high avidity to self antigen?
Strong TCR signal
Negative selection:
1. Apoptosis
2. Central colterance via CD4 T reg cell - regulates own immunity
What avidity does a TCR need to mature completely?
Intermediate avidity to self
These cells positively selected
Which MHC it reacts with determines CD4 vs CD8 expression
What is the goal of self selection?
NOT about peptide recognition
About MHC matching!
What is AIRE? Fxn, location, etc.
Autoimmune regulator
= TF
How thymus can express some self antigens from other tissues
How tissue specific genes are test outside that tissue
What kind of signal leads to negative selection of mature B cells? What is the goal of this step of B cell selection?
GOAL = humoral tolerance - Ab that binds monovalently - Undergoes clonal expansion - Immature IgMlo --> mature IgMhi Unknown or multivalent binding --> anergy or apoptosis
What happens if B cells produce an Ab that is self reactive?
Tested in bone marrow
Secondary rearrangement of LIGHT CHAIN only
Why are self reactive Abs common?
Because so many possibilities between the jointing genes of heavy and light chains
What is receptor editing?
TCR alpha and gamma & light chains (B cells)
Increases the chances of lymphocyte selection
Is clonality kept in allelic exclusion? In receptor editing?
AE: keep clonality
RE: no - but other mechanisms will likely maintain clonality
Does positive or negative selection occur first in T cell development? Where does each step happen?
1st = positive (alpha chain rearrange) @ thymus cortex 2nd = negative (interaction with medullary epithelium) @ medulla
What are the mechanisms of central vs peripheral tolerance?
Central - direct deletion of highly reactive T/B cells
Peripheral
1. Clonal anergy of self reactive T/B cells via costimulation
2. Suppression by Treg
Describe autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome.
AIRE mutation
No presentation of these tissue’s self antigen in the thymus
- Endocrine
- Epithelium
What happens if Foxp3 is mutated?
No Treg cells
Higher risk for:
- IBD
- Type 1 diabetes
