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MIIM30002 - Principles of Immunology > Lecture 20 - T cells - Development & Activation > Flashcards

Lecture 20 - T cells - Development & Activation Flashcards

1
Q

List some general features of T cell development

A

(Similar to B cells)
• Rearrangement of T cell receptor
• Testing for successful rearrangement
• Assembly of heterodimeric receptor

• Produced in BM but develop in thymus

Differences:
 • Two sets of TCR: αβ & γδ
 • More diverse subsets:
- helpers
- killers
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2
Q

What is important in terms of discovery about the thymus?

A

The last organ in the body to be ascribed a function

Function described in the 1950’s by Jacques Miller

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3
Q

What is DiGeorge Syndrome?

A
  • No thymus present - thymic aplasia

* Lack of T cells

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4
Q

Describe the time-frame of production of T cells

A
  • Highest levels occurring before puberty
  • Levels drop of markedly
  • Some low level of production occurring throughout life
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5
Q

What happens to the thymus at the onset of puberty?

A

Involutes

Becomes replaced by fatty tissue

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6
Q

Describe the structure of the thymus, including cell types in the various areas

A

• Capsule

Cortex: (superiorally)
• Thymocytes
• Cortical epithelial cells

Medulla: (inferiorally)
• Macrophages
• DCs
• HEV

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7
Q

Which types of cells from the BM enter the thymus?

How do they enter?

A
  • Thymocytes come from the BM

* Enter through HEVs

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8
Q

What are the fates of thymocytes?

A
  1. α/β T cells
  2. γ/δ T cells
  3. Invariant NKT cells
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9
Q

Where are γ/δ T cells found?

A

Mucosal surfaces
• Skin

Look like Langerhans cells

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10
Q

Which thymocyte derivatives have invariant usage of the TCR genes?

A

γ/δ T cells & Invariant NKT cells

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11
Q

Describe the progression of development of T cells

Describe what is happening at each of these stages

A
  1. DN1
    • TCR genes in germ line configuration

Thymocytes interact with cortical epithelial cells

  1. DN2
    • Dβ-Jβ rearrangement
    • Cells become responsive to IL-2 through up regulation of CD25
  2. DN3
    • Vβ-DβJβ rearrangement
    • Pre-TCR testing w/ pTα and CD3 once β is rearranged
  3. DN4
    • Proliferation of thymocytes with successful β chain rearrangement
  4. Double positive
    • Vα-Jα rearrangement
    • Positive selection
  5. Single positive
    • Either CD4+8- or CD4-8+
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12
Q

What is the role of IL-2 in T cell development?

When do T cells become responsive to it?

How do they becomes responsive to it?

A

Stimulates proliferation (growth factor)

Become responsive to IL-2 at the DN2 stage

Through expression of CD25 (α chain, high affinity IL-2R)

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13
Q

What is being tested at the Pre-TCR stage?

What happens if there is success?

A

Viability of the β chain rearrangement

If success:
• Signals to the nucleus to turn on CD4 and CD8 transcription
• Becomes double positive thymocyte

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14
Q

Describe the expression of CD4 and CD8 over time

A

Thymocytes: don’t express either
DN: don’t express either
DP: express both
SP: express one or the other, depending on what sort of stimulation was received

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15
Q

Which chain of the TCR is rearranged first?

A

β chain is rearranged first (it is like the heavy chain)

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16
Q

How does a T cell become responsive to IL-2?

A

CD25: α chain, rendering IL-2R high affinity

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17
Q

What is the hallmark of DN2?

A

Upregulation of CD25

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18
Q

When does a big burst of proliferation occur in B & T cell development?

Why does this occur?

A

B cell: once heavy chain has been rearranged

T cell: once β chain has been rearranged

This produces many clones, all with the same β chain (or heavy chain)
These clones all rearrange their light/α chain independently
The individual β chain can thus be used in many different TCRs

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19
Q

When does massive culling of T cells occur?

A

After rearrangement of β chain

Those cells that don’t produce successful chains are culled

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20
Q

Describe the different locations of the developing T cells

A

Medulla:
1. Thymocytes enter through HEV in medulla

Cortex:

  1. DN1 migrate up to cortex to interact w/ cortical epithelial cells
  2. DN2 → DN3
  3. DN3 → DN4 aka Double negative migrate down a bit

Medulla:
5. Mature CD4+ and CD8+ T cells in medulla

21
Q

What is a double positive thymocyte?

Compare this with double negative thymocytes

A

Double positive: Express both CD4 and CD8

Double negative: express neither CD4 or CD8

22
Q

Which non-immune cells in the cortex and the medulla of the thymus are really important for T cell development?

A

Cortex:
• Cortical epithelial cells

Medulla:
• Dendritic cells
• Medulla epithelial cells

23
Q

What is the structure of the pre-TCR?

A

β chain + pTα

24
Q

What is pTα?

A

Surrogate α chain

25
Q

Describe the process of TCR rearrangement

A
  1. Simultaneous rearrangement of γ, δ and β chains
  2. If a successful pre-TCR is formed, signals halt the rearrangement of γ & δ chains (allelic exclusion)
  3. Rearrangement of α chain locus

NB If β chain rearrangement is unsuccessful, it goes on to form γ:δ TCR

26
Q

What is the importance of the developing T cells going into the cortex of the thymus?

A

Positive selection

  • Here they interact with cortical thymic epithelial cells
  • It interacts with the MHC on the thymic stromal cells
  • If this works, then it gets a survival signal
  • All these thymocytes in the cortex are tested for their ability to interact with MHC
  • The antigen in the MHC is irrelevant at this stage

(It is not just the antigen that binds the TCR, but also the MHC molecule that is important)

27
Q

What are the various outcomes of the different affinities of TCR to MHC

A

Strong binding
• Likely to respond to self antigen
• Negatively selected

Intermediate binding: positively selected

No binding: ‘death by neglect’
• Do not receive the correct signals

28
Q

Compare which cells undergo the following:
• death by neglect
• positive
• negative selection

A

Positive selection: intermediate affinity

Negative selection: too high affinity

Death by neglect: no affinity

(affinity: TCR to MHC)

29
Q

What is the importance of DC’s in the medulla of the thymus?

A

Perform negative selection

If TCR binds any antigen presented (because there will only be self antigen at this stage)

30
Q

Compare the different outcomes when there is recognition of specific peptide + MHC by the TCR in the thymus and in the periphery

A

Thymus: deletion

Periphery: activation

31
Q

Describe how the periphery is represented in the thymus

A

• Transcription factor: AIRE
(Autoimmune regulator) in medullary epithelial cells (MEC)

• AIRE stimulates the transcription of all sorts of proteins that typically only occur in organs in the body
- pancreas
- eye
etc.

• These antigens are presented in the context of MHC by MECs and DCs in the medulla

32
Q

What is APECED?

Describe the clinical features as well as the pathogenesis

A

Autoimmune polyendocrine syndrome

Defect in AIRE gene

Experience weird diseases:
 • Problem w/ thyroid: very small thyroid & gonads
 • Lack pigments in skin
 • Lack hair
 • Struggle to absorb food
 • Anaemia
 • Hepatitis

This is all associated with T cell infiltrate

  • AIRE hasn’t exposed developing T cells to all the antigens around the body
  • T cells have not been negatively selected
  • Auto-reactive T cells destroy organs
33
Q

Describe the mechanism of lineage commitment (CD4/CD8) of α/β T cells

A
  1. Pre-TCR success signals → CD4 and CD8 expression
    CD4(high)CD8(high)
  2. Positive selection
  3. Down regulation of CD4 & CD8 expression
    CD4(low)CD8(low)
  4. CD4 re-expressed at low levels CD4(high)CD8(low)

5a. If the TCR, at this point, interacts with MHC II (ThPOK)
→ CD4 lineage

5b. If MHC I binds the TCR (no ThPOK), CD4 is repressed and CD8 is upregulated → CD8 lineage

34
Q

What do ‘DN’ and ‘DP’ stand for?

A

DN: double negative
DP: double positive

35
Q

What is the ‘default lineage’ of T cells?

A

CD4+ T cell

If binding of MHC II-TCR doesn’t happen, then CD4 expression is down regulated, and CD8 expression is upregulated

36
Q

Where (physically) does TCR rearrangement occur?

A

In the cortex of the thymus

37
Q

Why is CD25 important?

At what stage of T cell development is it seen?

A

Receptor for IL-2
Needed for proliferation and stimulation of growth
Present at the DN2 and DN3 stages

38
Q

What do CECs do?

A

Cortical epithelial cells

Positive selection
• of those T cells that have intermediate affinity for MHC expressed on the CECs

39
Q

Where does positive selection occur?

What about negative selection?

A

Positive: cortex
Negative: medulla

40
Q

Compare the role of the following cells in the thymic medulla:
• DC
• Medullary epithelial cell

A

MEC:
• AIRE expressed
• AIRE turns on transcription of many different genes
• Antigen from all over the body expressed
• Presentation of the antigen on MHC to DP thymocytes

DCs:
• Presentation of self antigens to DP thymocytes (Negative selection)

41
Q

At which stage is α chain rearrangement happening?

A

Double positive thymocyte

i.e. after pre-TCR testing at the DN3 stage

42
Q

At which stage is the pre-TCR checkpoint?

A

DN3

43
Q

Expression of which gene leads to the CD4 T cell lineage?

A

ThPOK

44
Q

When is α:β lineage committed?

A

At the DN3 stage

i.e. once successful rearrangement of the β chain occurs

45
Q

Which cell expresses AIRE?

A

Medullary epithelial cells in thymus

46
Q

Which cell performs negative selection on developing T cells?

A

DCs in medulla of thymus

47
Q

Which thymocytes are found in the medulla?

A

Only mature SP thymocytes

48
Q

What is happening at the DN4 stage?

A

T cells which successfully rearranged the beta chain under much proliferation

Each of these T cells independently rearranges the alpha chain.

This leads to maximising the probability that a T cell with a functional TCR will be produced

49
Q

Interaction with which cell leads to positive selection of DP thymocytes?

A

Cortical epithelial cells

MIIM30002 - Principles of Immunology (30 decks)

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