Lecture 19 - Early T Lymphocyte Maturation

Question 1

What does the absence of a thymus result in?

Answer 1

DiGeorge syndrome, thymic aplasia

Question 2

What happens to the thymus in puberty?

Answer 2

It involutes

Question 3

What is the thymus made of in adults?

Answer 3

Mostly fat

Question 4

Strange feature of mice without a thymus

Answer 4

They are bald. Mechanism unknown

Question 5

Which type of organ is the thymus?

Answer 5

Parenchymous

Question 6

How would you go about finding if new T cells are being made?

Answer 6

Search for excision circles of DNA.

Implies that RAG recombination is occurring

Question 7

What happens to T cell development in puberty?

Answer 7

It drops dramatically, but doesn’t cease.

Some new T cells are made throughout life

Question 8

How do thymocytes enter the thymus?

Answer 8

Through high endothelial venules

Question 9

Which cells develop in the bone marrow and make their way to the thymus?

Answer 9

Thymocytes

Question 10

What initiates T cell fate decision and proliferation in thymocytes?

Answer 10

Interaction with thymic stroma cells

Question 11

Three principal fates of thymocytes

Answer 11

1) Alpha/beta T cells
2) Gamma/delta T cels
3) Invariant NK T cells

Question 12

Alpha/beta T cells

Answer 12

Conventional T cells, further differentiate into CD4 or CD8

Question 13

Gamma/delta T cells
1)
2)
3)
4)

Answer 13

1) Primarily located at epithelial, mucosal sites
2) Lack CD4, CD8
3) Don’t undergo positive or negative selection
4) Produced earlier in development than other T cells

Question 14

What is T cell maturation tied to?

Answer 14

The histological structure of the thymus

Question 15

What is the state of the TCR locus in thymocytes when they enter the thymus?

Answer 15

Germline configuration

Unrecombined

Question 16

What happens in DN1?

Answer 16

TCR genes in germline configuration

Question 17

DN2

Answer 17

Thymocytes become responsive to IL-2 (because of CD25 expression)

Beta-chain rearrangement commences (Dbeta - Jbeta joining)

Question 18

DN3/4

Answer 18

Vbeta - DJbeta rearrangement

Pre-TCR testing tests whether cells express CD4 and CD8

Question 19

DP

Answer 19

Rearrangement begins at the alpha chain locus

A single rearranged beta chain can combine with many different alpha chains

Question 20

Cells important in thymocyte development

Answer 20

Cortical epithelial cells

Question 21

Which loci do double-negative thymocytes rearrange

Answer 21

Gamma, delta, beta simultaneously

Question 22

How do thymocytes become either alpha/beta or gamma/delta?
1)
2)
3)

Answer 22

1) If beta chain rearrangement is successful, pre-TCR is expressed (pTalpha is surrogate alpha chain)
2) This shuts of gamma/delta rearrangement
3) If beta chain doesn’t rearrange properly, gamma/delta rearrangement can continue

Question 23

How does beta chain rearrangement shut off gamma/delta rearrangement?
1)
2)

Answer 23

1) Pre-TCR dimerisation induces proliferation

2) RAG shut down, allelic exclusion initiated, excision of gamma/delta genes

Question 24

What is positive selection?

Answer 24

T cells are tested on their ability to bind self MHC

Question 25

How does positive selection take place?

Answer 25

T cells live for 3-4 days and then die, unless rescued by TCR engagement with MHC

Question 26

Which cells present MHC to DP thymocytes?

Answer 26

Thymic stromal cells (cortical epithelial)

Question 27

What determines MHC restriction of thymocytes?

Answer 27

Cortical epithelial cells

Question 28

What is negative selection for?

Answer 28

To prevent autoimmunity

Question 29

How does negative selection occur? 1) 2)

Answer 29

1) Professional antigen presenting cells (DCs) present self peptides on MHC molecules to thymocytes 2) If TCR binds too strongly, thymocyte is phagocytosed

Question 30

What is AIRE?

Answer 30

Generates antigens that look like self antigens (from genome) Used to negatively select thymocytes

Question 31

What is APECED?

Answer 31

Autoimmune polyendocrine syndrome No AIRE Leads to T cell infiltration of body sites, autoimmunity

Question 32

``` How does lineage commitment take place? 1) 2) 3) 4) ```

Answer 32

1) Upon MHC signals, CD4 and CD8 are downregulated 2) CD4 is expressed at low levels. If it binds to MHCII, Lck activation enhances CD4, suppresses CD8 3) If CD4 doesn't bind MHCII, CD8 binds MHCI, is upregulated 4) This results in single-positive T cells

Question 33

Where do DN1 and mature T lymphocytes reside?

Answer 33

Medulla of thymus

Question 34

Where are DN2, DN3/4 and immature double positive thymocytes?

Answer 34

Cortex of the thymus