Selection of T cell receptor repertoire and CD4/CD8 lineage commitment

Question 1

Briefly explain development of T cells?

Answer 1

Multipotent lymphoid progenitors migrate from bone marrow to thymus

Lymphoid progenitors commit to T cell lineage by turning into pre-t Cells

Pre t cell educated to self and non-self

Thymic selection and positively selected T cell leave thymus

Question 2

What cause lymphoid progenitors to migrate to the thymus from the blood marrow?

Answer 2

Chemokines travel through blood circulation and signals progenitors to follow to thymus

Question 3

What are the names of the chemokines that cause migration of progenitors to the thymus?

Answer 3

Chemokines

• thymosin
• thymotaxin
• thymopoetin
• thymic factors

Question 4

Which part of the thymus does late phase of T cell development take place in?

Answer 4

Medulla (lower lighter part)

Question 5

What cells are in the medulla?

Answer 5

Cortical epithelial cell and medullary epithelial cells
Lymphocytes
Dendritic cells and macrophages

Question 6

What is the hassal’s corpuscel?

Answer 6

Section of thymus where aggregation of mature lymphocytes occurs (esp Treg lymphocytes)

Question 7

In which direction of thymus does maturation of T cells take place in?

Answer 7

From top to bottom (from cortex (double negative) down to medulla (single positive)

Double positive in the middle on way down

Question 8

How do immature t cell become double positive?

Answer 8

Stromal cells interaction + singalled after beta cell rearrangment of TCR

Question 9

What else is expressed when immature T cell becomes double positive for CD4 and CD8?

Answer 9

CD3

Question 10

What does CD stand for?

Answer 10

Cluster differentiation

Question 11

How does population od T cell population subsets vary in differet lymphoid tissue?

Answer 11

In thymus, most are double postive and in spleen most are double negative but alot are mature and single positive

Question 12

Does positive or negative selection happen first?

Answer 12

Positive selection

Question 13

When are gamma delta t cell made?

Answer 13

Favoured during foetal development, drops after gestation and alpha beta rises

Question 14

What is different about gd T cells to ab T cells?

Answer 14

gd T cells aren’t MHC restricted, antigen can be recognised directly almost like an antibody

Question 15

When do gd T cell levels rise in humans after gestation?

Answer 15

Upregulated during stress conditions

Question 16

What do gd cells recongise in humans now’?

Answer 16

Phospholipid antigen on mycobacterium tuberculosis

+also role in cancer surveillance

Question 17

Which part of T cell development does D-J gene reassortment take place?

Answer 17

Double negative pre-TCR and proliferation

Question 18

Which part of T cell development does V-DJ gene reassortment take place?

Answer 18

Proliferation of pre T cells during double negative stage

Question 19

Which part of T cell development does V-J gene reassortment take place?

Answer 19

Double positive stage before they become single positive (alpha rearrangment finishes off)

Question 20

What events need to happen for a double positive thymocyte to become a single positive thymocyte?

Answer 20

Functional TCR alpha chain rearrangment
CD4 and MHC 2 complex formation (to become CD4+)
CD8 and MHC 1 complex formation (to become CD8+)
ERK signalling
Calcineurin signalling

Question 21

What happens to cells that do not complete thymocyte maturation (from double to single positive)?

Answer 21

Become apoptotic (DNA disintegration) during +ve and -ve selection and cleared by macrophages

Question 22

How many doubel positive T cells do not end up failing becoming single positive and apoptose?

Answer 22

95% of thymocytes

Question 23

Why are failed thymyocytes killed by apoptosis?

Answer 23

Controlled cell death doesnt cause damage to other cells/tissue

Question 24

What is the mechanism of apoptosis of failed thymyocytes?

Answer 24

Fas molecules on surface and Fas ligand (FasL)required before caspase cascade occurs causing chromatin disintegration and DNA break up

Question 25

Where are MHC 1 bearing cells found in the thymus?

Answer 25

Thymic stromal cells and low level on antigen presenting cells(DC and macrophages)

Question 26

Where are MHC 2 bearing cells found in the thymus?

Answer 26

Thymic medullary stromal cells and high level on antigen presenting cells

Question 27

Which HLAs are MHC class 1?

Answer 27

HLA A, HLA B, HLA C

Question 28

Which HLAs are MHC class 2?

Answer 28

HLR DR, HLA DQ, HLA DP

Question 29

What molecules are present on a double positive T cell?

Answer 29

CD4 and CD8 and T cell receptor

Question 30

What causes positive selection of T cells?

Answer 30

Double positive T cells bind to self MHC/HLA molecules, if strong there are positively selected

Question 31

What cause negative selection of T cells?

Answer 31

Weak or no binding of T cell receptors to self MHC/HLA molecules

Question 32

Where are the self MHC molecules that DP cells bind to?

Answer 32

Epithelial cells or APCs

Question 33

Is MHC class 1 or MHC class 2 binding more common?

Answer 33

Random, whichever the double positive finds first e.g. CD4 binds to HLA DR on thymic epithelial cells or CD8 binds to HLA 1 on thymic epithelial cells

Question 34

Why is positive selection important?

Answer 34

for self restriction - ensures only useful T cells that are able to recongise are selected

Question 35

What happens after one of the 2 CD coreceptors bind to a HLA molecule?

Answer 35

The other CD coreceptor is downregulated

Question 36

What happens to cells after positive selection?

Answer 36

Positively selected cells ready for negative selection whilst unselected cells dye via apoptosis

Question 37

What is the purpose of negative selection?

Answer 37

exclude self reactive t cells - cant react to self antigens from the random gene arrangement formed TCRs

Question 38

Which cells in thymus express self antigens?

Answer 38

Medulla - epithelial stromal cells or infiltrating dendritic cells/macrophages

Question 39

What happens if T cells bind to a self antigen in the medulla?

Answer 39

Possibility of that T cell being self reactive so it is removed by apoptosis

If weak binding and not dangerous it is selected - so based on affinity

Question 40

What happens to the selected cells from negative selection?

Answer 40

Some of them go onto become regulatory T cels

Question 41

Why is it important to destory self reactive T cells?

Answer 41

Will cause autoimmunity otherwise

Question 42

What happens to self reactive T cells before they are apoptosed?

Answer 42

Receptor editing - They go through further TCR rearrangments (mentioned earlier multiple gene rearrangments not just once), only removed if self reactive again

Question 43

How are T cells made to be not self reactive to self antigens from other organs as well (not just thymus cells self antigens)?

Answer 43

AIRE gene (autoimmune regulator) 
- a transcription activator gene in thmys allows expression of other tissue specific proteins so negative selection done against most body self antigens

Question 44

Which parts of bodies self antigens arent expressed by AIRE gene?

Answer 44

Brain and testes

Question 45

What do regulatory T cells that develop in thymus express?

Answer 45

CD25 and Foxp3

Question 46

How are Treg cells made?

Answer 46

In thymus but do not proliferate in response to self MHC peptide complexes,

Question 47

Where are treg cell found?

Answer 47

In hassal’s corpuscles of thymus and later migrates to diff tissue for response once pathogen is gone and effector t cell is no longer needed

Question 48

What is he role of Treg cells?

Answer 48

Dampen T cell response

Question 49

What is an immunological synapse?

Answer 49

Interaction formed between T cells and antigen presenting cell( perhaps containing target antigen for T cell to become effective)

Question 50

What happens to T cells in circulation if they don’t find a target antigen?

Answer 50

Die by apoptosis