Lecture 5 Adaptive Immunity - T Cell Development Flashcards
What is tolerance?
Self vs Non-self
-recognizing non-self and non harmful
What is negative selection?
If new B/T-cell binds self antigen this is a sign of autoimmunity
-results in receptor editing or apoptosis
What is a thymocyte?
immature T Cell
What co-receptors do T Cells express? What do they do?
CD4
-For MHC II and endogenous antigens
CD8
-For MHC I and exogenous antigens
What do you need to active a T Cell?
- Antigen
- Self MHC
Where does T Cell development occur? What do thymocytes undergo?
Bone marrow precursor cells migrate to thymus Thymocytes undergo
- TCR gene rearrangement
- TCR expression
- Co-receptor expression
- Positive selection for MHC restriction
- Negative selection for self-tolerance
How are TCR and BCR gene rearrangement similar?
One gene for each chain
- V-D-J-C segments
- RAG recombinase for gene recombination
- Artemis and TdT for junctional diversity
Alpha Chain = V-J-C
Beta Chain = V-D-J-C
What are the checkpoints for TCR co-receptor expression?
The thymocyte first undergoes TCR Beta gene rearrangement
-Double Negative
The thymocyte then tests Beta chain with Pre-T Alpha surrogate chain to see if functional
- if non-functional then 2nd allele tried
- either good or apoptosis
If Beta chain good then Alpha chain expressed and tested
-If good then you have a functional T cell
The functional T cell expresses CD4 and CD8 co-receptors
-Double positive
MHC restriction occurs next determines whether T cell will express CD4 or CD8
-Single positive
Next steps are MHC Restriction and Self Tolerance
What is MHC restriction?
Occurs in Thymic Cortex
Functional T Cells express TCR and are double positive expressing CD4 and CD8
Cortical Thymic Epithelial Cells (cTEC) are APC’s and present antigen peptides with self MHC I and MHC II
- antigen DOESN’T matter at this point
- looking for WEAK binding affinity
- too strong = bad
Positive Selection
- If binding occurs then survival occurs
- If no binding or too strong then death or death by neglect
Bottom Line
- DP Thymocytes enter thymic cortex
- cTEC APC’s present antigen peptides
- weak or low binding affinity = survival (pos selection)
- Immature Single positive thymocyte exits thymic cortex and enter thymic medulla
What kind of selection is MHC Restriction?
Positive selection
- cell survival if TCR has low affinity binding to self MHC Negative selection
- cell death if TCR has high affinity binding to self MHC
What is death by neglect?
cell death because TCR has no binding to self MHC
Why is high binding affinity bad in MHC restriction?
TCR might bind MHC w/o antigen present
May not be able to dissociate from antigen
How does a double positive thymocyte choose which kind of co-receptor to express and become a single positive thymocyte?
The MHC I or MHC II the thymocyte binds on the cTEC will determine whether CD4 or CD8 is expressed
What is the CD3 complex?
Stabilizes the TCR alpha and beta chains in the cell membrane Generates intracellular signals
- if weak binding occurs then DP to SP thymocyte
- if strong or no binding occurs then induce apoptosis or death by neglect
How is self tolerance generated in T Cells?
Immature SP thymocytes express TCR and EITHER CD4 or CD8 Medullary Thymic Epithelial Cells (mTEC) and Dendritic Cells present self antigens with MHC I or MHC II
- the antigens ARE important now b/c we know TCR works with self MHC Covers MOST self antigens
- AIRE covers the rest
- allows mTEC to express antigens from other areas of the body Results in Mature Naive CD4 or CD8 T lymphocytes
Go through the process of T Cell Development.
