Lecture 5 Adaptive Immunity - T Cell Development

Question 1

What is tolerance?

Answer 1

Self vs Non-self

-recognizing non-self and non harmful

Question 2

What is negative selection?

Answer 2

If new B/T-cell binds self antigen this is a sign of autoimmunity

-results in receptor editing or apoptosis

Question 3

What is a thymocyte?

Answer 3

immature T Cell

Question 4

What co-receptors do T Cells express? What do they do?

Answer 4

CD4

-For MHC II and endogenous antigens

CD8

-For MHC I and exogenous antigens

Question 5

What do you need to active a T Cell?

Answer 5

1. Antigen
2. Self MHC

Question 6

Where does T Cell development occur? What do thymocytes undergo?

Answer 6

Bone marrow precursor cells migrate to thymus Thymocytes undergo

1. TCR gene rearrangement
2. TCR expression
3. Co-receptor expression
4. Positive selection for MHC restriction
5. Negative selection for self-tolerance

Question 7

How are TCR and BCR gene rearrangement similar?

Answer 7

One gene for each chain

1. V-D-J-C segments
2. RAG recombinase for gene recombination
3. Artemis and TdT for junctional diversity

Alpha Chain = V-J-C

Beta Chain = V-D-J-C

Question 8

What are the checkpoints for TCR co-receptor expression?

Answer 8

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

Question 9

What is MHC restriction?

Answer 9

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

Question 10

What kind of selection is MHC Restriction?

Answer 10

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

Question 11

What is death by neglect?

Answer 11

cell death because TCR has no binding to self MHC

Question 12

Why is high binding affinity bad in MHC restriction?

Answer 12

TCR might bind MHC w/o antigen present

May not be able to dissociate from antigen

Question 13

How does a double positive thymocyte choose which kind of co-receptor to express and become a single positive thymocyte?

Answer 13

The MHC I or MHC II the thymocyte binds on the cTEC will determine whether CD4 or CD8 is expressed

Question 14

What is the CD3 complex?

Answer 14

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

Question 15

How is self tolerance generated in T Cells?

Answer 15

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

Question 16

What kind of selection is Self Tolerance?

Answer 16

Positive Selection

-cell survival when TCR does not bind to self antigens

Negative Selection

-cell death when TCR binds to self antigens

Question 17

How are the different antigens present in the body presented to immature T lymphocytes in the thymic medulla to develop self tolerance?

Answer 17

Central Tolerance

• Medullary Thymic Epithelial Cells, mTEC present antigens present within the thymic medulla
• Dendritic Cells present self antigens that circulate through thymus

Peripheral Tolerance

-Autoimmune Regulator, AIRE, allow mTEC to express antigen peptides present in other parts of the body Tolerance creates mature naive tolerance

Question 18

How does Autoimmune Regulator Transcription Factor work to allow mTEC to present antigen peptides not present in the thymus?

Answer 18

Turns on genes that are normally turned off in thymus

-transcription and translation mTEC then presents these antigens to develop peripheral tolerance

Question 19

What are the two MAJOR checkpoints in T Cell development?

Answer 19

1. MHC restriction
2. Self Tolerance

At each stage binding of TCR results in different intracellular signal and outcome

Question 20

Go through the process of T Cell Development.

Answer 20