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IMIN 371 > T Cell Development l > Flashcards

T Cell Development l Flashcards

1
Q

Where do T cells originate and develop?

A

originate = bone marrow
develop = thymus

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2
Q

What are developing T cells referred to as?

A

thymocytes

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3
Q

How long does T cell development take?

A

1-3 weeks

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4
Q

Describe the size of the thymus as human development occurs.

A

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

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5
Q

Describe the lobular structures of the thymus

A

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

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6
Q

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

A
  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)
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7
Q

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

A
  1. TCR dependent
  2. positive selection
  3. negative selecton
  4. CD4+ or CD8+ lineage commitment
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8
Q

What is positive selection?

A

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

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9
Q

What is negative selection?

A

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

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10
Q

What is CD4+ or CD8+ lineage commitment?

A

thymocytes become CD4+ or CD8+

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11
Q

What are some other names for T cell precursors?

A
  1. thymus-settling progenitors (TSPs)
  2. double negative 1 (DN1) cells
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12
Q

How are T cell precursors directed to the thymus?

A

via cytokines

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13
Q

What are DN stages defined by?

A

lack of CD4 and CD8 expression

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14
Q

How are the four DN stages distinguished?

A

by cell surface markers

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15
Q

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

A

DN2

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16
Q

What TFs are expressed when a T cell commits?

A

Notch and GATA-3

17
Q

At what DN stage does Beta selection occur?

A

DN2

18
Q

Describe the ordered progression of TCR rearrangements

A
  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
19
Q

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

A

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

20
Q

What is beta selection?

A

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

21
Q

What stage of B cell development does beta selection resemeble?

A

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

22
Q

How does pre-TCR signaling occur?

A

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

23
Q

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

A
  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)
24
Q

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

A

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

found in the cortex of the thymus

25
Q

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

A
  1. positive selection
  2. negative selection
  3. lineage commitment
26
Q

What is education?

A

The process of positive and negative selection in the thymus

27
Q

Why do T cells have to go under education?

A

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

28
Q

What cells mediate positive selection of thymocytes?

A

corticol thymic epithelial cells (cTECs)

29
Q

What is MHC restriction?

A

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

30
Q

What cells mediate negative selection?

A

cTECs and DCs

31
Q

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

A

Negative selection in the thymus

32
Q

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

A
  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

33
Q

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

A
  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
34
Q

Why are so many thymocytes lost by death by neglect?

A

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

IMIN 371 (20 decks)

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