T Cell Development l

Question 1

Where do T cells originate and develop?

Answer 1

originate = bone marrow
develop = thymus

Question 2

What are developing T cells referred to as?

Answer 2

thymocytes

Question 3

How long does T cell development take?

Answer 3

1-3 weeks

Question 4

Describe the size of the thymus as human development occurs.

Answer 4

at birth = thymus is fully developed
at peak puberty = thymus at greatest size
after peak puberty = thymus atrophies

Question 5

Describe the lobular structures of the thymus

Answer 5

lobular structures are seperated by a capsule, each capsule contains an outer cortex and an inner medulla

Question 6

What are some characterisitics/events of early T cell development?

Answer 6

1. TCR independent
2. precursors come from bone marrow and develop in the thymus
3. TCR rearrangement begins in an ordered progression
4. expansion of T cell precursors that successfully rearrange the TCR beta chain and can form the pre-TCR (beta selection)

Question 7

What are some characteristics/events of late T cell development?

Answer 7

1. TCR dependent
2. positive selection
3. negative selecton
4. CD4+ or CD8+ lineage commitment

Question 8

What is positive selection?

Answer 8

selection for cells whose TCRs can interact with self-MHC/self-peptides with intermediate affinity

Question 9

What is negative selection?

Answer 9

selection against cells with TCRs that strongly interact with self-MHC/self-peptides

Question 10

What is CD4+ or CD8+ lineage commitment?

Answer 10

thymocytes become CD4+ or CD8+

Question 11

What are some other names for T cell precursors?

Answer 11

1. thymus-settling progenitors (TSPs)
2. double negative 1 (DN1) cells

Question 12

How are T cell precursors directed to the thymus?

Answer 12

via cytokines

Question 13

What are DN stages defined by?

Answer 13

lack of CD4 and CD8 expression

Question 14

How are the four DN stages distinguished?

Answer 14

by cell surface markers

Question 15

At what stage can T cell precursors no longer give rise to other lineages?

Answer 15

DN2

Question 16

What TFs are expressed when a T cell commits?

Answer 16

Notch and GATA-3

Question 17

At what DN stage does Beta selection occur?

Answer 17

DN2

Question 18

Describe the ordered progression of TCR rearrangements

Answer 18

1. beta chain and delta and gamma chain start rearranging
2. if beta chain has a successful rearrangement, the alpha chain will begin rearranging
3. if both the delta and gamma chain successfully rearrange before the beta chain, the T cell will become a gamma/delta T cell

Question 19

At what stage is the pre-TCR expressed, and what is the pre-TCR?

Answer 19

stage = starts at DN3 and continues into DN4
pre-TCR = functional beta chain + pre-Talpha + CD3

Question 20

What is beta selection?

Answer 20

selection for a functional beta chain that can bind pre-Talpha and form the pre-TCR

Question 21

What stage of B cell development does beta selection resemeble?

Answer 21

pre-B cell stage -> functional rearrangement of the H chain

Question 22

How does pre-TCR signaling occur?

Answer 22

Ligand-independent: expression of the pre-TCR on the surface is sufficient for pre-TCR signaling

Question 23

What are the four developmental signals that the pre-TCR provides?

Answer 23

1. cell becomes permissive for TCR alpha chain locus rearrangment
2. stimulates expression of CD4 and CD8
3. stimulates proliferation
4. stops additional TCR beta chain locus rearrangements (allelic exclusion)

Question 24

What are the defining features of a DP T cell? And where are these cells found

Answer 24

alpha/beta TCR expressed on the surface with both CD4 and CD8

found in the cortex of the thymus

Question 25

What are the important checkpoints that occur at the DP stage?

Answer 25

1. positive selection 2. negative selection 3. lineage commitment

Question 26

What is education?

Answer 26

The process of positive and negative selection in the thymus

Question 27

Why do T cells have to go under education?

Answer 27

T cells recognize Ag in the context of self-MHC; therefore, they must have TCRs that bind self-MHC, but at the same time not cause autoimmunity

Question 28

What cells mediate positive selection of thymocytes?

Answer 28

corticol thymic epithelial cells (cTECs)

Question 29

What is MHC restriction?

Answer 29

developing thymocytes learn what is self MHC and become restricted to recognize peptides in the context of self-MHC

Question 30

What cells mediate negative selection?

Answer 30

cTECs and DCs

Question 31

What process in T cell development is an example of central tolerance?

Answer 31

Negative selection in the thymus

Question 32

Describe the experimental evidence for cTECs mediating MHC restricition. What was the conclusion made?

Answer 32

1. H2a/a mother and a H2b/b father (haplotypes) were crossed 2. the H2a/b progeny had their thymus removed and exposed to lethal x-radiation which removed bone-marrow derived cells including HSCs 3. A thymus that is H2b/b was irridated to remove the thymocytes (epithelial cells were not affected) and HSCs (H2a/b) were transplanted into the mice 4. the mice were infected with LCMV (a virus) 5. spleen cells which include mature T cells were removed and cultured on two plates: one where all the cells are H2a/a and one where all the cells were H2b/b, and each plate was infected with LCMV 6. LCMV H2a/a cells were not killed, LCMV H2b/b cells were killed conclusion: non-lymphoid cells of the thymus (cTECs) mediate MHC restriction

Question 33

Describe the four different fates that T cells will fall into during education.

Answer 33

1. death by neglect - majority of cells - little or no affinity - cells undergo apoptosis 2. positive selection - intermediate affinity - 2-5% of cells 3. agonist selection - some strong self-reactive thymocytes adopt a different fate - Treg or other fates 4. negative selection - strong affinity - 2-5% - most cells deleted through clonal deletion, but some anergy and receptor editing

Question 34

Why are so many thymocytes lost by death by neglect?

Answer 34

TCR gene rearrangements are random; therefore, more likely that a TCR will have little to no affinity for self-MHC + self-peptide