Lecture 19 - Early T Lymphocyte Maturation Flashcards

1
Q

What does the absence of a thymus result in?

A

DiGeorge syndrome, thymic aplasia

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2
Q

What happens to the thymus in puberty?

A

It involutes

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3
Q

What is the thymus made of in adults?

A

Mostly fat

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4
Q

Strange feature of mice without a thymus

A

They are bald. Mechanism unknown

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5
Q

Which type of organ is the thymus?

A

Parenchymous

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6
Q

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

A

Search for excision circles of DNA.

Implies that RAG recombination is occurring

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7
Q

What happens to T cell development in puberty?

A

It drops dramatically, but doesn’t cease.

Some new T cells are made throughout life

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8
Q

How do thymocytes enter the thymus?

A

Through high endothelial venules

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9
Q

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

A

Thymocytes

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10
Q

What initiates T cell fate decision and proliferation in thymocytes?

A

Interaction with thymic stroma cells

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11
Q

Three principal fates of thymocytes

A

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

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12
Q

Alpha/beta T cells

A

Conventional T cells, further differentiate into CD4 or CD8

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13
Q
Gamma/delta T cells
1)
2)
3)
4)
A

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

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14
Q

What is T cell maturation tied to?

A

The histological structure of the thymus

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15
Q

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

A

Germline configuration

Unrecombined

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16
Q

What happens in DN1?

A

TCR genes in germline configuration

17
Q

DN2

A

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

Beta-chain rearrangement commences (Dbeta - Jbeta joining)

18
Q

DN3/4

A

Vbeta - DJbeta rearrangement

Pre-TCR testing tests whether cells express CD4 and CD8

19
Q

DP

A

Rearrangement begins at the alpha chain locus

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

20
Q

Cells important in thymocyte development

A

Cortical epithelial cells

21
Q

Which loci do double-negative thymocytes rearrange

A

Gamma, delta, beta simultaneously

22
Q

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

A

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

23
Q

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

A

1) Pre-TCR dimerisation induces proliferation

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

24
Q

What is positive selection?

A

T cells are tested on their ability to bind self MHC

25
Q

How does positive selection take place?

A

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

26
Q

Which cells present MHC to DP thymocytes?

A

Thymic stromal cells (cortical epithelial)

27
Q

What determines MHC restriction of thymocytes?

A

Cortical epithelial cells

28
Q

What is negative selection for?

A

To prevent autoimmunity

29
Q

How does negative selection occur?
1)
2)

A

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

30
Q

What is AIRE?

A

Generates antigens that look like self antigens (from genome)

Used to negatively select thymocytes

31
Q

What is APECED?

A

Autoimmune polyendocrine syndrome

No AIRE

Leads to T cell infiltration of body sites, autoimmunity

32
Q
How does lineage commitment take place?
1)
2)
3)
4)
A

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

33
Q

Where do DN1 and mature T lymphocytes reside?

A

Medulla of thymus

34
Q

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

A

Cortex of the thymus