Antigen Receptor Signaling and T-cell Activation - Kane Flashcards

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1
Q

What is Lck and what is its function?

A

Lck is a Src tyrosine kinase closely associated with the co-receptors of T-cells and plays a role in the phosphorylation cascades involved in TCR signaling.

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2
Q

TCR signaling: Step 1

A

TCR binds to MHC-peptide and co-receptor brings Lck to close proximity of ITAMs

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3
Q

TCR signaling: Step 2

A

Lck phosphorylates ITAMs in zeta chains and CD3 chains of the TCR.

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4
Q

TCR signaling: Step 3

A

Zap70 is recruited to ITAM phosphorylated tyrosines and Zap70 gets phosphorylated by Lck.

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5
Q

TCR signaling: Step 4

A

Zap70 phosphorylates LAT and PLCy1, and PLCy1 associates with LAT

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6
Q

TCR signaling: Step 5

A

PLCy1 cleaves phosphoinositol substrates and creates second messengers such as DAG and IP3

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7
Q

TCR signaling: Step 6

A

Second messengers activate txn factors such as NF-AT

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8
Q

What is an SH2 domain and what does it do?

A

SH2 domains are specific regions of proteins that can mediate direct binding of phosphorylated tyrosine substrates. For example, SH2 domains Zap70 can bind to z-chains phosphorylated by Lck.

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9
Q

What is an SH3 domain?

A

SH3 domains are specific regions of proteins that recognize poly-proline residues.

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10
Q

Describe the PLCy1 pathway

A

Upon activation of PLCy1, it cleaves PIP to generate 2 second messengers, DAG and IP3.

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11
Q

What does IP3 do?

A

IP3 is a second messenger that associates with the ER and causes an efflux of intracellular Ca. Efflux of Ca, causes activation of calcineurin which dephosphorylates NF-AT (txn factor).

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12
Q

What do the drugs cyclophilin and FKBP do?

A

These drugs inhibit calcineurin preventing activation of NF-AT. This shuts down T-cell activation despite upstream signaling.

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13
Q

Describe co-stimulation of T-cells?

A

CD28 on T-cells interact with B7 receptors on APCs to stimulate activation. Absence of this signal can lead to a state of anergy.

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14
Q

How is co-stimulation regulated? Describe how this is druggable.

A

CTLA on T-cells regulate stimulation by B7 on APCs by competitively inhibiting CD28. Drugs such as CTLA-Ig can competitively inhibit B7 to prevent co-stimulation of T-cells.

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15
Q

How can you enhance T-cell responses via drugs involved in the co-stimulation pathway?

A

You can target CTLA to inhibit it so that it cannot dampen co-stimulation of T-cells via CD28 and B7 interactions.

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16
Q

What is LFA1?

A

Adhesion molecule constitutively expressed on T-cells that interact with ICAMs on APCs to stabilize TCR interaction with MHC-peptide.

17
Q

What cytokine is critical for T-cell activation and proliferation?

A

IL-2. This cytokine is upregulated in activated T-cells and can act in an auto or paracrine fashion to stimulate T-cell proliferation.

18
Q

How do CD4+ T-cells help other immune cells?

A

They bind to and secrete cytokines to enhance effector functions of phagocytes. They can also stimulate B-cells to secrete antibodies.

19
Q

How is the T-cell response resolved (down-regulated)

A

Apoptosis of T-cells following the acute phase of the response.

20
Q

What are the features of lymphocyte memory?

A

Higher precursor frequency (decreases proliferation time). Shorter activation time.

21
Q

What is T-cell exhaustion?

A

During a chronic infection or cancer where repeated stimulation of T-cells impedes the development of memory T-cells.

22
Q

Which proteins direct T-cell circulation?

A

L-Selectin interacting with modified sugars on epithelial cells or lymph node venules. Naiive and activated T-cells express different adhesion molecules.

23
Q

What do chemokines do?

A

Small molecules that cause chemotaxis to direct immune cells or promote inflammation of tissues to promote infiltration of immune cells to tissues.

24
Q

What are some methods to track phosphorylation in cells?

A

P32 orthophosphate - radioactive or Phospho-specific antibodies (4G10 –> tyrosine phos.).

25
Q

Western blotting vs. Flow cytometry

A

Western blots have a disadvantage as its a lot of steps and lots of samples but better visualization of band sizes. Flow uses small number of cells and visualization of sub-pops but more complicated controls.

26
Q

Visualizing activation of transcription factors?

A

Transcriptional reporters

27
Q

How can you measure T-cell proliferation?

A

Monitoring DNA replication in stimulated T-cells with labeled nucleotides.